HAEM5:T-large granular lymphocytic leukaemia: Difference between revisions

[unchecked revision]

Latest revision as of 20:10, 16 January 2026

Haematolymphoid Tumours (WHO Classification, 5th ed.)

This page is under construction

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:T-cell Large Granular Lymphocytic Leukemia.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Michelle Don, MD, MS
Nicolas LaScala, DO

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	T-cell and NK-cell lymphoid proliferations and lymphomas
Family	Mature T-cell and NK-cell neoplasms
Type	Mature T-cell and NK-cell leukaemias
Subtype(s)	T-large granular lymphocytic leukaemia

Related Terminology


Acceptable	T-cell lymphoproliferative disease of granular lymphocytes; T-cell large granular lymphocytic leukaemia
Not Recommended	T-cell large granular lymphocytosis; T-gamma lymphoproliferative disease

Gene Rearrangements

No know chromosomal rearrangements. (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A

editv4:Chromosomal Rearrangements (Gene Fusions)

The content below was from the old template. Please incorporate above.

End of V4 Section

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

Please incorporate this section into the relevant tables found in:
Chromosomal Rearrangements (Gene Fusions)

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal Patterns

Gene Mutations (SNV/INDEL)

End of V4 Section

Individual Region Genomic Gain/Loss/LOH

No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in a few cases.^[1] (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
N/A	N/A	N/A	N/A	N/A	N/A	N/A

editv4:Genomic Gain/Loss/LOH

The content below was from the old template. Please incorporate above.

End of V4 Section

Characteristic Chromosomal or Other Global Mutational Patterns

No characteristic chromosomal patterns have been identified. One reported case with unique cytogenetic findings of a γδ variant T-cell LGL include: interstitial deletion of 3p21.31, monosomy X, trisomy 5, monosomy 21, and CN-LOH, located at 17q.^[2] (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
N/A	N/A	N/A	N/A	N/A	N/A

editv4:Characteristic Chromosomal Aberrations / Patterns

The content below was from the old template. Please incorporate above.

End of V4 Section

Gene Mutations (SNV/INDEL)

Somatic activating STAT3 and STAT5b mutations are the most common SNVs in T-LGL. (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
STAT3^[3]	Gain of function in src-like homologue 2 (SH2) domain of STAT 3, frequently affecting codons Y640 or D661^[3]^. Codons N647I^[4],K658S^[4], and K658F^[5] are also affected	Other ^[6]	Common ^[7]	D, P, T	WHO, NCCN	STAT3 mutation has been associated with statistically significant neutropenia, thrombocytopenia, and reduced numbers of most normal residual blood-leukocyte subsets^[5] STAT3 mutations are associated with a worse prognosis and reduced overall survival ^[3]^[8] Patients with STAT 3 mutation required treatment more frequently when compared to patients with STAT3 wild type^[9] One prospective study showed a predictive response to methotrexate therapy in a small group of patients with STAT3 Y640F mutated genotype^[10] STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma^[11] 17% of patients with STAT3 mutations, had multiple mutations in the STAT3 gene, solely in cytotoxic CD8+ or NK cells.^[12]
STAT5B ^[3]	Gain of function src-like homologue 2 (SH2) domain of STAT5. Mutations include^[13]: N642H Y665F Q706L S715F T628S P685R V712E mutation of STAT5B is in the transactivation domain^[13] Mutations in the coiled-coil domain: CCD, Q220H ^[13] Mutations in the DNA binding domain: DBD, E433G/K ^[13] Mutations in the inter-domain region: P702A ^[13]	Other ^[14]	Rare ^[1]	D,P,T	WHO, NCCN	N642H mutation (associated with more aggressive disease)^[15]^[16] Clones can acquire multiple STAT5B mutations ^[13] STAT5B mutations can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma^[11] N642H mutation is associated with CD3+/CD56+ phenotype^[16] STAT5B mutations are more common in CD4+ T-LGLL than in CD8+ T-LGLL ^[13]^[17]
TNFAIP3 ^[3]	Loss of function Somatic mutations: Y353X K354K Q741 E630X A717T F127C ^[18]	Other ^[19]	Recurrent ^[20]	P,T	WHO	TNFAIP 3 mutation has been correlated with increased overall survival ^[21] TNFAIP3 itself is a NF‐κB target gene^[22] In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (p = 0.004)^[4]
TET2 ^[3]	Loss of function ^[23]	Other ^[24]	Common ^[20]	N/A	WHO	Found to be the most prevalent mutation in myeloid neoplasm or myeloid clonal hematopoiesis coexisting with T-LGLL ^[25]
BCL11B ^[3]	Missense H126R^[26]	Other^[27]	Rare^[26]	N/A	WHO	BCL11B is required for T-cell survival and overexpression could effectively increase T-cell activation and proliferation.^[26]
FLT3^[3]	A high-impact Asp228Gly variant on JAK STAT has been demonstrated ^[28]	Other^[29]	Rare^[28]	N/A	WHO	Connects STAT to the MAPK-Ras-ERK pathway and to IL-15^[28]
PTPN23^[3]	R641Q^[30]	Other^[31]	Rare^[30]	N/A	WHO	Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation^[30]
KMT2D^[23]	Loss of function^[23]	Other^[32]	Recurrent^[20]	N/A	None	KMT2D has been linked to lymphomagenesis.^[28] KMT2D has been how to exhibit significant co-occurrence with STAT3 mutation^[23]
TRAF3 ^[25]	c.650A>T p.E217V^[25]	Other^[33]	Rare^[25]	N/A	None	Mutated putative driver^[25]
CLIP3^[25]	c.908A>T p.D303V c.917A>T p.K306M^[25]	Other^[34]	Rare^[25]	N/A	None	Mutated putative driver^[25]
FBXW2^[25]	c.683C>G p.A228G ^[25]	Other^[35]	Rare^[25]	N/A	None	Mutated putative driver^[25]
CREBBP^[25]	c.1178A>G p.N393S c.4306T>C p.C1436R^[25]	Other^[36]	Rare^[25]	N/A	None	Mutated putative driver ^[25]
CCL2 ^[37]	SNV, somatic Mutation P46R^[37]	Other^[38]	Rare^[37]	N/A	None	CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL^[37] CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL^[37]

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

The content below was from the old template. Please incorporate above.

End of V4 Section

Epigenomic Alterations

Epigenetic inactivation of JAK/STAT pathway inhibitors
- SOCS3 has a crucial role in regulating STAT3 activation^[39]
- An epigenetic inhibition mechanism to SOCS3 gene is hypothesized^[39]
- KIR3DL1 has been shown to be down-modulated by hypermethylation of the promoter^[39]
- Mutations in KMT2D and TET2 have been found to significantly co-occur with STAT3 mutations^[23]

Genes and Main Pathways Involved

(Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
JAK/STAT^[1]	Constitutive activation	Dysregulation of apoptosis
NK-kB^[1]	Pathway activation	Preventing apoptosis
FAS and FASL^[1]	Resistance to FAS mediated apoptosis	Activation of pro-survival pathways which is postulated to lead to neutropenia
RAS/RAF1/MEK1/ERK^[1]	Overactive RAS	Constitutive activation of RAS and ERK
PI3K/AKT^[1]	Dysregulation	Apoptosis inhibition

editv4:Genes and Main Pathways Involved

The content below was from the old template. Please incorporate above.

End of V4 Section

Genetic Diagnostic Testing Methods

Morphologic assessment, flow cytometry and immunohistochemistry
PCR to assess for clonality, T-cell receptor (TCR) gene rearrangements
- TCR gamma (TCRG) gene is rearranged in all cases, regardless of the type of TCR expressed, thus proves clonality^[3]
- Can be helpful in differentiating a reactive lymphocytosis from clonal T-LGL's
  - NK LGL proliferations do not express TCR, making assessment of clonality difficult^[1]
  - Expression of activating isoforms of killer immunoglobulin-like receptors (KIR) can be used as a surrogate marker of clonality in NK LGL^[1]
Myeloid neoplasms may present with clonal large granular lymphocyte expansion with STAT3/STAT5B mutations. Next generation sequencing can be diagnostically useful in these cases^[40]

Familial Forms

No known familiar forms as of yet.

Additional Information

PI3K-Akt has been found to be upregulated in KLRG1^- CD8⁺ T-LGLL. Studies are being conducted to examine treatment with linperlisib.^[41]
Myleoid clonal hematopoiesis is associated with the presence of cytopenia in LGLL^[25]

Links

Hepatosplenic T-cell lymphoma

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)

↑ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4 ^1.5 ^1.6 ^1.7 ^1.8 Lamy, Thierry; et al. (2017-03-02). "LGL leukemia: from pathogenesis to treatment". Blood. 129 (9): 1082–1094. doi:10.1182/blood-2016-08-692590. ISSN 0006-4971.
↑ Zhang, Ling; et al. (2014-09). "Transformed aggressive γδ‐variant T‐cell large granular lymphocytic leukemia with acquired copy neutral loss of heterozygosity at 17q11.2q25.3 and additional aberrations". European Journal of Haematology. 93 (3): 260–264. doi:10.1111/ejh.12313. ISSN 0902-4441. Check date values in: |date= (help)
↑ ^3.00 ^3.01 ^3.02 ^3.03 ^3.04 ^3.05 ^3.06 ^3.07 ^3.08 ^3.09 "BlueBooksOnline".
↑ ^4.0 ^4.1 ^4.2 Johansson, Patricia; et al. (2016-01-01). "Recurrent alterations of TNFAIP 3 (A20) in T-cell large granular lymphocytic leukemia: A20 mutations in T-LGL". International Journal of Cancer. 138 (1): 121–124. doi:10.1002/ijc.29697.
↑ ^5.0 ^5.1 Muñoz-García, Noemí; et al. (2020-11-25). "STAT3 and STAT5B Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features". Cancers. 12 (12): 3508. doi:10.3390/cancers12123508. ISSN 2072-6694. PMC 7760806 Check |pmc= value (help). PMID 33255665 Check |pmid= value (help).
↑ "STAT3 signal transducer and activator of transcription 3 [Homo sapiens (human)] - Gene - NCBI".
↑ Koskela, Hanna L.M.; et al. (2012-05-17). "Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia". New England Journal of Medicine. 366 (20): 1905–1913. doi:10.1056/NEJMoa1114885. ISSN 0028-4793.
↑ Barilà, Gregorio; et al. (2020-04). "Stat3 mutations impact on overall survival in large granular lymphocyte leukemia: a single-center experience of 205 patients". Leukemia. 34 (4): 1116–1124. doi:10.1038/s41375-019-0644-0. ISSN 0887-6924. Check date values in: |date= (help)
↑ Fei, Fei; et al. (2023-07-29). "Genomic landscape of T-large granular lymphocyte leukemia and chronic lymphoproliferative disorder of NK cells: a single institution experience". Leukemia & Lymphoma. 64 (9): 1536–1544. doi:10.1080/10428194.2023.2220450. ISSN 1042-8194.
↑ Loughran, T P; et al. (2015-04). "Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998)". Leukemia. 29 (4): 886–894. doi:10.1038/leu.2014.298. ISSN 0887-6924. PMC 4377298. PMID 25306898. Check date values in: |date= (help)
↑ ^11.0 ^11.1 Yabe, Mariko; et al. (2017-01). "Distinguishing Between Hepatosplenic T-cell Lymphoma and γδ T-cell Large Granular Lymphocytic Leukemia: A Clinicopathologic, Immunophenotypic, and Molecular Analysis". American Journal of Surgical Pathology. 41 (1): 82–93. doi:10.1097/PAS.0000000000000743. ISSN 0147-5185. Check date values in: |date= (help)
↑ Rajala HL, Olson T, Clemente MJ, Lagström S, Ellonen P, Lundan T, Hamm DE, Zaman SA, Marti JM, Andersson EI, Jerez A. The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia. haematologica. 2015 Jan 1;100(1):91-9.
↑ ^13.0 ^13.1 ^13.2 ^13.3 ^13.4 ^13.5 ^13.6 Bhattacharya, Dipabarna; et al. (2022-02-24). "Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia". Blood Cancer Journal. 12 (2): 31. doi:10.1038/s41408-022-00630-8. ISSN 2044-5385. PMC 8873566 Check |pmc= value (help). PMID 35210405 Check |pmid= value (help).
↑ "STAT5B signal transducer and activator of transcription 5B [Homo sapiens (human)] - Gene - NCBI".
↑ Rajala, Hanna L. M.; et al. (2013-05-30). "Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia". Blood. 121 (22): 4541–4550. doi:10.1182/blood-2012-12-474577. ISSN 0006-4971. PMC 3668487. PMID 23596048.
↑ ^16.0 ^16.1 Rajala, Hanna L. M.; et al. (2014-05-01). "Uncovering the pathogenesis of large granular lymphocytic leukemia—novel STAT3 and STAT5b mutations". Annals of Medicine. 46 (3): 114–122. doi:10.3109/07853890.2014.882105. ISSN 0785-3890.
↑ Andersson, Emma I.; et al. (2016-11-17). "High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia". Blood. 128 (20): 2465–2468. doi:10.1182/blood-2016-06-724856. ISSN 0006-4971. PMC 5114490. PMID 27697773.
↑ Johansson, Patricia; et al. (2016-01-01). "Recurrent alterations of TNFAIP 3 (A20) in T-cell large granular lymphocytic leukemia: A20 mutations in T-LGL". International Journal of Cancer. 138 (1): 121–124. doi:10.1002/ijc.29697.
↑ "TNFAIP3 TNF alpha induced protein 3 [Homo sapiens (human)] - Gene - NCBI".
↑ ^20.0 ^20.1 ^20.2 Upadhyayula, Bhanu Surabi; et al. (2026-01). "Mutational Spectrum of T-Cell Large Granular Lymphocytic Leukemia: Insights From the AACR Project GENIE Consortium". Cancer Genomics - Proteomics. 23 (1): 135–143. doi:10.21873/cgp.20566. ISSN 1109-6535. PMC 12758657 Check |pmc= value (help). PMID 41482347 Check |pmid= value (help). Check date values in: |date= (help)
↑ Chen, Cunte; et al. (2021-09-15). "TNFAIP3 mutation may be associated with favorable overall survival for patients with T-cell lymphoma". Cancer Cell International. 21 (1): 490. doi:10.1186/s12935-021-02191-5. ISSN 1475-2867. PMC 8444556 Check |pmc= value (help). PMID 34526012 Check |pmid= value (help).
↑ Zhang, Ranran; et al. (2008-10-21). "Network model of survival signaling in large granular lymphocyte leukemia". Proceedings of the National Academy of Sciences. 105 (42): 16308–16313. doi:10.1073/pnas.0806447105. PMC 2571012. PMID 18852469.
↑ ^23.0 ^23.1 ^23.2 ^23.3 ^23.4 Cheon, HeeJin; et al. (2022-05-19). "Genomic landscape of TCRαβ and TCRγδ T-large granular lymphocyte leukemia". Blood. 139 (20): 3058–3072. doi:10.1182/blood.2021013164. ISSN 0006-4971. PMC 9121841 Check |pmc= value (help). PMID 35015834 Check |pmid= value (help).
↑ "TET2 tet methylcytosine dioxygenase 2 [Homo sapiens (human)] - Gene - NCBI".
↑ ^25.00 ^25.01 ^25.02 ^25.03 ^25.04 ^25.05 ^25.06 ^25.07 ^25.08 ^25.09 ^25.10 ^25.11 ^25.12 ^25.13 ^25.14 ^25.15 ^25.16 ^25.17 Kawashima, Naomi; et al. (2025-02). "Clonal hematopoiesis in large granular lymphocytic leukemia". Leukemia. 39 (2): 451–459. doi:10.1038/s41375-024-02460-y. ISSN 1476-5551. Check date values in: |date= (help)
↑ ^26.0 ^26.1 ^26.2 Andersson, E. I.; et al. (2013-12). "Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation". Blood Cancer Journal. 3 (12): e168–e168. doi:10.1038/bcj.2013.65. ISSN 2044-5385. PMC 3877422. PMID 24317090. Check date values in: |date= (help)
↑ "BCL11 transcription factor B".
↑ ^28.0 ^28.1 ^28.2 ^28.3 Coppe, A; et al. (2017-05). "Genomic landscape characterization of large granular lymphocyte leukemia with a systems genetics approach". Leukemia. 31 (5): 1243–1246. doi:10.1038/leu.2017.49. ISSN 0887-6924. PMC 5419584. PMID 28167832. Check date values in: |date= (help)
↑ "fms related receptor tyrosine kinase 3".
↑ ^30.0 ^30.1 ^30.2 Andersson, Emma I.; et al. (2016-11-17). "High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia". Blood. 128 (20): 2465–2468. doi:10.1182/blood-2016-06-724856. ISSN 0006-4971. PMC 5114490. PMID 27697773.
↑ "protein tyrosine phosphatase non-receptor type 23".
↑ "KMT2D lysine methyltransferase 2D [Homo sapiens (human)] - Gene - NCBI".
↑ "TRAF3 TNF receptor associated factor 3 [Homo sapiens (human)] - Gene - NCBI".
↑ "TRAF3 TNF receptor associated factor 3 [Homo sapiens (human)] - Gene - NCBI".
↑ "F-box and WD repeat domain containing 2".
↑ "CREBBP CREB binding lysine acetyltransferase [Homo sapiens (human)] - Gene - NCBI".
↑ ^37.0 ^37.1 ^37.2 ^37.3 ^37.4 Mizuno, Yuga; et al. (2024-05-30). "CCL22 mutations in large granular lymphocytic leukemia". Haematologica. doi:10.3324/haematol.2024.285404. ISSN 1592-8721. PMC 11367240 Check |pmc= value (help). PMID 38813714 Check |pmid= value (help).
↑ "C-C motif chemokine ligand 2".
↑ ^39.0 ^39.1 ^39.2 Teramo, Antonella; et al. (2013-05-09). "Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia". Blood. 121 (19): 3843–3854, S1. doi:10.1182/blood-2012-07-441378. ISSN 1528-0020. PMID 23515927.
↑ Kavesh, Mark; et al. (2023-01-10). "Distinguishing STAT3/STAT5B -mutated large granular lymphocyte leukemia from myeloid neoplasms by genetic profiling". Blood Advances. 7 (1): 40–45. doi:10.1182/bloodadvances.2022008192. ISSN 2473-9529.
↑ Zhang, Lele; et al. (2025-04). "KLRG1 re-defines a leukemic clone of CD8 effector T cells sensitive to PI3K inhibitor in T cell large granular lymphocytic leukemia". Cell Reports Medicine. 6 (4): 102036. doi:10.1016/j.xcrm.2025.102036. PMC 12047471 Check |pmc= value (help). PMID 40147444 Check |pmid= value (help). Check date values in: |date= (help)

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):

*Citation of this Page: “T-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 01/16/2026, https://ccga.io/index.php/HAEM5:T-large_granular_lymphocytic_leukaemia.

Other Sections

Cancer Category

Mature T- and NK-cell Neoplasm

[:3-1] 1.0 ^1.1 ^1.2 ^1.3 ^1.4 ^1.5 ^1.6 ^1.7 ^1.8 Lamy, Thierry; et al. (2017-03-02). "LGL leukemia: from pathogenesis to treatment". Blood. 129 (9): 1082–1094. doi:10.1182/blood-2016-08-692590. ISSN 0006-4971.

[2] Zhang, Ling; et al. (2014-09). "Transformed aggressive γδ‐variant T‐cell large granular lymphocytic leukemia with acquired copy neutral loss of heterozygosity at 17q11.2q25.3 and additional aberrations". European Journal of Haematology. 93 (3): 260–264. doi:10.1111/ejh.12313. ISSN 0902-4441. Check date values in: |date= (help)

[:9-3] 3.00 ^3.01 ^3.02 ^3.03 ^3.04 ^3.05 ^3.06 ^3.07 ^3.08 ^3.09 "BlueBooksOnline".

[:11-4] 4.0 ^4.1 ^4.2 Johansson, Patricia; et al. (2016-01-01). "Recurrent alterations of TNFAIP 3 (A20) in T-cell large granular lymphocytic leukemia: A20 mutations in T-LGL". International Journal of Cancer. 138 (1): 121–124. doi:10.1002/ijc.29697.

[:12-5] 5.0 ^5.1 Muñoz-García, Noemí; et al. (2020-11-25). "STAT3 and STAT5B Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features". Cancers. 12 (12): 3508. doi:10.3390/cancers12123508. ISSN 2072-6694. PMC 7760806 Check |pmc= value (help). PMID 33255665 Check |pmid= value (help).

[6] "STAT3 signal transducer and activator of transcription 3 [Homo sapiens (human)] - Gene - NCBI".

[7] Koskela, Hanna L.M.; et al. (2012-05-17). "Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia". New England Journal of Medicine. 366 (20): 1905–1913. doi:10.1056/NEJMoa1114885. ISSN 0028-4793.

[8] Barilà, Gregorio; et al. (2020-04). "Stat3 mutations impact on overall survival in large granular lymphocyte leukemia: a single-center experience of 205 patients". Leukemia. 34 (4): 1116–1124. doi:10.1038/s41375-019-0644-0. ISSN 0887-6924. Check date values in: |date= (help)

[9] Fei, Fei; et al. (2023-07-29). "Genomic landscape of T-large granular lymphocyte leukemia and chronic lymphoproliferative disorder of NK cells: a single institution experience". Leukemia & Lymphoma. 64 (9): 1536–1544. doi:10.1080/10428194.2023.2220450. ISSN 1042-8194.

[10] Loughran, T P; et al. (2015-04). "Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998)". Leukemia. 29 (4): 886–894. doi:10.1038/leu.2014.298. ISSN 0887-6924. PMC 4377298. PMID 25306898. Check date values in: |date= (help)

[:13-11] 11.0 ^11.1 Yabe, Mariko; et al. (2017-01). "Distinguishing Between Hepatosplenic T-cell Lymphoma and γδ T-cell Large Granular Lymphocytic Leukemia: A Clinicopathologic, Immunophenotypic, and Molecular Analysis". American Journal of Surgical Pathology. 41 (1): 82–93. doi:10.1097/PAS.0000000000000743. ISSN 0147-5185. Check date values in: |date= (help)

[:4-12] Rajala HL, Olson T, Clemente MJ, Lagström S, Ellonen P, Lundan T, Hamm DE, Zaman SA, Marti JM, Andersson EI, Jerez A. The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia. haematologica. 2015 Jan 1;100(1):91-9.

[:14-13] 13.0 ^13.1 ^13.2 ^13.3 ^13.4 ^13.5 ^13.6 Bhattacharya, Dipabarna; et al. (2022-02-24). "Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia". Blood Cancer Journal. 12 (2): 31. doi:10.1038/s41408-022-00630-8. ISSN 2044-5385. PMC 8873566 Check |pmc= value (help). PMID 35210405 Check |pmid= value (help).

[14] "STAT5B signal transducer and activator of transcription 5B [Homo sapiens (human)] - Gene - NCBI".

[15] Rajala, Hanna L. M.; et al. (2013-05-30). "Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia". Blood. 121 (22): 4541–4550. doi:10.1182/blood-2012-12-474577. ISSN 0006-4971. PMC 3668487. PMID 23596048.

[:15-16] 16.0 ^16.1 Rajala, Hanna L. M.; et al. (2014-05-01). "Uncovering the pathogenesis of large granular lymphocytic leukemia—novel STAT3 and STAT5b mutations". Annals of Medicine. 46 (3): 114–122. doi:10.3109/07853890.2014.882105. ISSN 0785-3890.

[17] Andersson, Emma I.; et al. (2016-11-17). "High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia". Blood. 128 (20): 2465–2468. doi:10.1182/blood-2016-06-724856. ISSN 0006-4971. PMC 5114490. PMID 27697773.

[18] Johansson, Patricia; et al. (2016-01-01). "Recurrent alterations of TNFAIP 3 (A20) in T-cell large granular lymphocytic leukemia: A20 mutations in T-LGL". International Journal of Cancer. 138 (1): 121–124. doi:10.1002/ijc.29697.

[19] "TNFAIP3 TNF alpha induced protein 3 [Homo sapiens (human)] - Gene - NCBI".

[:16-20] 20.0 ^20.1 ^20.2 Upadhyayula, Bhanu Surabi; et al. (2026-01). "Mutational Spectrum of T-Cell Large Granular Lymphocytic Leukemia: Insights From the AACR Project GENIE Consortium". Cancer Genomics - Proteomics. 23 (1): 135–143. doi:10.21873/cgp.20566. ISSN 1109-6535. PMC 12758657 Check |pmc= value (help). PMID 41482347 Check |pmid= value (help). Check date values in: |date= (help)

[21] Chen, Cunte; et al. (2021-09-15). "TNFAIP3 mutation may be associated with favorable overall survival for patients with T-cell lymphoma". Cancer Cell International. 21 (1): 490. doi:10.1186/s12935-021-02191-5. ISSN 1475-2867. PMC 8444556 Check |pmc= value (help). PMID 34526012 Check |pmid= value (help).

[22] Zhang, Ranran; et al. (2008-10-21). "Network model of survival signaling in large granular lymphocyte leukemia". Proceedings of the National Academy of Sciences. 105 (42): 16308–16313. doi:10.1073/pnas.0806447105. PMC 2571012. PMID 18852469.

[:0-23] 23.0 ^23.1 ^23.2 ^23.3 ^23.4 Cheon, HeeJin; et al. (2022-05-19). "Genomic landscape of TCRαβ and TCRγδ T-large granular lymphocyte leukemia". Blood. 139 (20): 3058–3072. doi:10.1182/blood.2021013164. ISSN 0006-4971. PMC 9121841 Check |pmc= value (help). PMID 35015834 Check |pmid= value (help).

[24] "TET2 tet methylcytosine dioxygenase 2 [Homo sapiens (human)] - Gene - NCBI".

[:1-25] 25.00 ^25.01 ^25.02 ^25.03 ^25.04 ^25.05 ^25.06 ^25.07 ^25.08 ^25.09 ^25.10 ^25.11 ^25.12 ^25.13 ^25.14 ^25.15 ^25.16 ^25.17 Kawashima, Naomi; et al. (2025-02). "Clonal hematopoiesis in large granular lymphocytic leukemia". Leukemia. 39 (2): 451–459. doi:10.1038/s41375-024-02460-y. ISSN 1476-5551. Check date values in: |date= (help)

[:17-26] 26.0 ^26.1 ^26.2 Andersson, E. I.; et al. (2013-12). "Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation". Blood Cancer Journal. 3 (12): e168–e168. doi:10.1038/bcj.2013.65. ISSN 2044-5385. PMC 3877422. PMID 24317090. Check date values in: |date= (help)

[27] "BCL11 transcription factor B".

[:18-28] 28.0 ^28.1 ^28.2 ^28.3 Coppe, A; et al. (2017-05). "Genomic landscape characterization of large granular lymphocyte leukemia with a systems genetics approach". Leukemia. 31 (5): 1243–1246. doi:10.1038/leu.2017.49. ISSN 0887-6924. PMC 5419584. PMID 28167832. Check date values in: |date= (help)

[29] "fms related receptor tyrosine kinase 3".

[:19-30] 30.0 ^30.1 ^30.2 Andersson, Emma I.; et al. (2016-11-17). "High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia". Blood. 128 (20): 2465–2468. doi:10.1182/blood-2016-06-724856. ISSN 0006-4971. PMC 5114490. PMID 27697773.

[31] "protein tyrosine phosphatase non-receptor type 23".

[32] "KMT2D lysine methyltransferase 2D [Homo sapiens (human)] - Gene - NCBI".

[33] "TRAF3 TNF receptor associated factor 3 [Homo sapiens (human)] - Gene - NCBI".

[34] "TRAF3 TNF receptor associated factor 3 [Homo sapiens (human)] - Gene - NCBI".

[35] "F-box and WD repeat domain containing 2".

[36] "CREBBP CREB binding lysine acetyltransferase [Homo sapiens (human)] - Gene - NCBI".

[:2-37] 37.0 ^37.1 ^37.2 ^37.3 ^37.4 Mizuno, Yuga; et al. (2024-05-30). "CCL22 mutations in large granular lymphocytic leukemia". Haematologica. doi:10.3324/haematol.2024.285404. ISSN 1592-8721. PMC 11367240 Check |pmc= value (help). PMID 38813714 Check |pmid= value (help).

[38] "C-C motif chemokine ligand 2".

[:10-39] 39.0 ^39.1 ^39.2 Teramo, Antonella; et al. (2013-05-09). "Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia". Blood. 121 (19): 3843–3854, S1. doi:10.1182/blood-2012-07-441378. ISSN 1528-0020. PMID 23515927.

[40] Kavesh, Mark; et al. (2023-01-10). "Distinguishing STAT3/STAT5B -mutated large granular lymphocyte leukemia from myeloid neoplasms by genetic profiling". Blood Advances. 7 (1): 40–45. doi:10.1182/bloodadvances.2022008192. ISSN 2473-9529.

[41] Zhang, Lele; et al. (2025-04). "KLRG1 re-defines a leukemic clone of CD8 effector T cells sensitive to PI3K inhibitor in T cell large granular lymphocytic leukemia". Cell Reports Medicine. 6 (4): 102036. doi:10.1016/j.xcrm.2025.102036. PMC 12047471 Check |pmc= value (help). PMID 40147444 Check |pmid= value (help). Check date values in: |date= (help)

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

HAEM5:T-large granular lymphocytic leukaemia: Difference between revisions

Latest revision as of 20:10, 16 January 2026

Contents

Primary Author(s)*

WHO Classification of Disease

Related Terminology

Gene Rearrangements

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal or Other Global Mutational Patterns

Gene Mutations (SNV/INDEL)

Epigenomic Alterations

Genes and Main Pathways Involved

Genetic Diagnostic Testing Methods

Familial Forms

Additional Information

Links

References

Notes

Other Sections

Navigation menu

@@ Line 4: / Line 4: @@
 {{Under Construction}}
-<blockquote class='blockedit'>{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:T-cell Large Granular Lymphocytic Leukemia]].
+<blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:T-cell Large Granular Lymphocytic Leukemia]].
 }}</blockquote>
-<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
+<span style="color:#0070C0">(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)</span>
 ==Primary Author(s)*==
 *Michelle Don, MD, MS
-__TOC__
+*Nicolas LaScala, DO
 ==WHO Classification of Disease==
@@ Line 36: / Line 36: @@
 |}
-==Definition / Description of Disease==
+==Related Terminology==
+{| class="wikitable"
+|+
+|Acceptable
+|T-cell lymphoproliferative disease of granular lymphocytes; T-cell large granular lymphocytic leukaemia
+|-
+|Not Recommended
+|T-cell large granular lymphocytosis; T-gamma lymphoproliferative disease
+|}
+==Gene Rearrangements==
+No know chromosomal rearrangements. <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
+{| class="wikitable sortable"
+|-
+!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
+!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
+!Clinical Relevance Details/Other Notes
+|-
+|N/A||N/A||N/A||N/A
+|N/A
+|N/A
+|N/A
+|N/A
+|}
-*Increased peripheral blood large granular lymphocytes (LGLs) for >6 months without a identifiable cause
+<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
-*Chronic and often indolent T-cell proliferation
+*
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":0">Chan W.C., et al., (2017). T-cell large granular lymphocytic leukemia, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p 348-350.</ref><blockquote class="blockedit">
+<blockquote class="blockedit">
 <center><span style="color:Maroon">'''End of V4 Section'''</span>
 ----
 </blockquote>
-==Synonyms / Terminology==
-*T-cell large granular lymphocytic leukemia
-==Epidemiology / Prevalence==
+<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
+* Chromosomal Rearrangements (Gene Fusions)
+* Individual Region Genomic Gain/Loss/LOH
+* Characteristic Chromosomal Patterns
+* Gene Mutations (SNV/INDEL)}}</blockquote>
+*
-*2-3% of mature small lymphocytic leukemias
+<blockquote class="blockedit">
-*Male:Female ~ 1:1
-*Most commonly occurs between ages 45-75 years old
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":0" /><blockquote class="blockedit">
 <center><span style="color:Maroon">'''End of V4 Section'''</span>
 ----
 </blockquote>
-==Clinical Features==
+==Individual Region Genomic Gain/Loss/LOH==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
+No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in a few cases.<ref name=":3">{{Cite journal|last=Lamy|first=Thierry|last2=Moignet|first2=Aline|last3=Loughran|first3=Thomas P.|date=2017-03-02|title=LGL leukemia: from pathogenesis to treatment|url=https://ashpublications.org/blood/article/129/9/1082/36568/LGL-leukemia-from-pathogenesis-to-treatment|journal=Blood|language=en|volume=129|issue=9|pages=1082–1094|doi=10.1182/blood-2016-08-692590|issn=0006-4971}}</ref> <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
-{| class="wikitable"
+{| class="wikitable sortable"
-|'''Signs and Symptoms'''
+|-
-|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
+!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
-<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
+!Clinical Relevance Details/Other Notes
-<span class="blue-text">EXAMPLE:</span> Fatigue
-<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
 |-
-|'''Laboratory Findings'''
+|N/A
-|<span class="blue-text">EXAMPLE:</span> Cytopenias
+|N/A
+|N/A
-<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
+|N/A
+|N/A
+|N/A
+|N/A
 |}
+<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
-<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}</blockquote>
+*
-*Severe neutropenia
-*Lymphocyte count usually 2-20x10<sup>9</sup>/L
-*Has been reported to occur with:
-**Severe red cell hypoplasia
-**Rheumatoid arthritis
-**Low grade B-cell malignancies
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":0" /><blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
 <blockquote class="blockedit">
 <center><span style="color:Maroon">'''End of V4 Section'''</span>
 ----
 </blockquote>
-</blockquote>
+==Characteristic Chromosomal or Other Global Mutational Patterns==
-==Sites of Involvement==
-*Peripheral blood and bone marrow
-*Spleen - infiltration and expansion of red pulp
-*Liver
-*Skin (rare)
-*Lymph nodes (exceptional)
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":0" /><blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Morphologic Features==
-Large granular lymphocytes
-*Moderate to abundant cytoplasm
-*Fine or course azurophilic granules
-==Immunophenotype==
+No characteristic chromosomal patterns have been identified. One reported case with unique cytogenetic findings of a γδ variant T-cell LGL include: interstitial deletion of 3p21.31, monosomy X, trisomy 5, monosomy 21, and CN-LOH, located at 17q.<ref>{{Cite journal|last=Zhang|first=Ling|last2=Ramchandren|first2=Radhakrishnan|last3=Papenhausen|first3=Peter|last4=Loughran|first4=Thomas P.|last5=Sokol|first5=Lubomir|date=2014-09|title=Transformed aggressive γδ‐variant T‐cell large granular lymphocytic leukemia with acquired copy neutral loss of heterozygosity at 17q11.2q25.3 and additional aberrations|url=https://onlinelibrary.wiley.com/doi/10.1111/ejh.12313|journal=European Journal of Haematology|language=en|volume=93|issue=3|pages=260–264|doi=10.1111/ejh.12313|issn=0902-4441}}</ref> <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
 {| class="wikitable sortable"
 |-
-!Finding!!Marker
+!Chromosomal Pattern
+!Molecular Pathogenesis
+!Prevalence -
+Common >20%, Recurrent 5-20% or Rare <5% (Disease)
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
+!Clinical Relevance Details/Other Notes
 |-
-|Positive||CD8, CD2, CD3, CD16, CD57, αβ (alpha-beta) TCR
+|N/A
-Cytotoxic effector proteins: TIA1, Granzyme B, Granzyme M
+|N/A
-|-
+|N/A
-|Negative||CD4, CD5, CD7
+|N/A
-|-
+|N/A
-|Please note:||
+|N/A
-*Cases of CD4+ LGL leukemia has been described<ref>Lima M, Almeida J, dos Anjos Teixeira M, del Carmen Alguero M, Santos AH, Balanzategui A, Queirós ML, Bárcena P, Izarra A, Fonseca S, Bueno C. TCRαβ+/CD4+ large granular lymphocytosis: a new clonal T-cell lymphoproliferative disorder. The American journal of pathology. 2003 Aug 1;163(2):763-71.</ref>
+|}
-*Cases of CD4-/CD8-, γδ (gamma-delta) T-LGL leukemia has also been described (<5% of cases)<ref>Chen YH, Chadburn A, Evens AM, Winter JN, Gordon LI, Chenn A, Goolsby C, Peterson L. Clinical, morphologic, immunophenotypic, and molecular cytogenetic assessment of CD4–/CD8–γδ T-cell large granular lymphocytic leukemia. American journal of clinical pathology. 2011 Aug 1;136(2):289-99.</ref>
-|}
+<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
+***
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":0" /><blockquote class="blockedit">
+<blockquote class="blockedit">
 <center><span style="color:Maroon">'''End of V4 Section'''</span>
 ----
 </blockquote>
-==Chromosomal Rearrangements (Gene Fusions)==
+==Gene Mutations (SNV/INDEL)==
-Put your text here and fill in the table
+Somatic activating STAT3 and STAT5b mutations are the most common SNVs in T-LGL.  <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
 {| class="wikitable sortable"
 |-
-!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
+!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
-!Diagnostic Significance (Yes, No or Unknown)
+Common >20%, Recurrent 5-20% or Rare <5% (Disease)
-!Prognostic Significance (Yes, No or Unknown)
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
-!Therapeutic Significance (Yes, No or Unknown)
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
-!Notes
+!Clinical Relevance Details/Other Notes
 |-
-|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
+|''STAT3''<ref name=":9">{{Cite journal|title=BlueBooksOnline|url=https://tumourclassification.iarc.who.int/chapters/63}}</ref>
-<span class="blue-text">EXAMPLE:</span> 30% (add reference)
+|Gain of function in src-like homologue 2 (SH2) domain of STAT 3, frequently affecting codons Y640 or D661<ref name=":9" /><sup>.</sup> Codons N647I<ref name=":11">{{Cite journal|last=Johansson|first=Patricia|last2=Bergmann|first2=Anke|last3=Rahmann|first3=Sven|last4=Wohlers|first4=Inken|last5=Scholtysik|first5=René|last6=Przekopowitz|first6=Martina|last7=Seifert|first7=Marc|last8=Tschurtschenthaler|first8=Gertraud|last9=Webersinke|first9=Gerald|date=2016-01-01|title=Recurrent alterations of TNFAIP 3 (A20) in T-cell large granular lymphocytic leukemia: A20 mutations in T-LGL|url=https://onlinelibrary.wiley.com/doi/10.1002/ijc.29697|journal=International Journal of Cancer|language=en|volume=138|issue=1|pages=121–124|doi=10.1002/ijc.29697}}</ref>,K658S<ref name=":11" />, and K658F<ref name=":12">{{Cite journal|last=Muñoz-García|first=Noemí|last2=Jara-Acevedo|first2=María|last3=Caldas|first3=Carolina|last4=Bárcena|first4=Paloma|last5=López|first5=Antonio|last6=Puig|first6=Noemí|last7=Alcoceba|first7=Miguel|last8=Fernández|first8=Paula|last9=Villamor|first9=Neus|date=2020-11-25|title=STAT3 and STAT5B Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features|url=https://www.mdpi.com/2072-6694/12/12/3508|journal=Cancers|language=en|volume=12|issue=12|pages=3508|doi=10.3390/cancers12123508|issn=2072-6694|pmc=7760806|pmid=33255665}}</ref> are also affected
-|Yes
+|Other <ref>{{Cite journal|title=STAT3 signal transducer and activator of transcription 3 [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/6774}}</ref>
-|No
+|Common <ref>{{Cite journal|last=Koskela|first=Hanna L.M.|last2=Eldfors|first2=Samuli|last3=Ellonen|first3=Pekka|last4=van Adrichem|first4=Arjan J.|last5=Kuusanmäki|first5=Heikki|last6=Andersson|first6=Emma I.|last7=Lagström|first7=Sonja|last8=Clemente|first8=Michael J.|last9=Olson|first9=Thomas|date=2012-05-17|title=Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia|url=http://www.nejm.org/doi/abs/10.1056/NEJMoa1114885|journal=New England Journal of Medicine|language=en|volume=366|issue=20|pages=1905–1913|doi=10.1056/NEJMoa1114885|issn=0028-4793}}</ref>
-|Yes
+|D, P, T
-|<span class="blue-text">EXAMPLE:</span>
+|WHO, NCCN
+|STAT3 mutation has been associated with statistically significant neutropenia, thrombocytopenia, and reduced numbers of most normal residual blood-leukocyte subsets<ref name=":12" />
-The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
+STAT3 mutations are associated with a worse prognosis and reduced overall survival <ref name=":9" /><ref>{{Cite journal|last=Barilà|first=Gregorio|last2=Teramo|first2=Antonella|last3=Calabretto|first3=Giulia|last4=Vicenzetto|first4=Cristina|last5=Gasparini|first5=Vanessa Rebecca|last6=Pavan|first6=Laura|last7=Leoncin|first7=Matteo|last8=Vedovato|first8=Susanna|last9=Frigo|first9=Anna Chiara|date=2020-04|title=Stat3 mutations impact on overall survival in large granular lymphocyte leukemia: a single-center experience of 205 patients|url=https://www.nature.com/articles/s41375-019-0644-0|journal=Leukemia|language=en|volume=34|issue=4|pages=1116–1124|doi=10.1038/s41375-019-0644-0|issn=0887-6924}}</ref>
-|}
-<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
-*No known chromosomal rearrangements
-<blockquote class="blockedit">
+Patients with STAT 3 mutation required treatment more frequently when compared to patients with STAT3 wild type<ref>{{Cite journal|last=Fei|first=Fei|last2=Stehr|first2=Henning|last3=Zehnder|first3=James L.|date=2023-07-29|title=Genomic landscape of T-large granular lymphocyte leukemia and chronic lymphoproliferative disorder of NK cells: a single institution experience|url=https://www.tandfonline.com/doi/full/10.1080/10428194.2023.2220450|journal=Leukemia & Lymphoma|language=en|volume=64|issue=9|pages=1536–1544|doi=10.1080/10428194.2023.2220450|issn=1042-8194}}</ref>
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
+One prospective study showed a predictive response to methotrexate therapy in a small group of patients with STAT3 Y640F mutated genotype<ref>{{Cite journal|last=Loughran|first=T P|last2=Zickl|first2=L|last3=Olson|first3=T L|last4=Wang|first4=V|last5=Zhang|first5=D|last6=Rajala|first6=H L M|last7=Hasanali|first7=Z|last8=Bennett|first8=J M|last9=Lazarus|first9=H M|date=2015-04|title=Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998)|url=https://www.nature.com/articles/leu2014298|journal=Leukemia|language=en|volume=29|issue=4|pages=886–894|doi=10.1038/leu.2014.298|issn=0887-6924|pmc=4377298|pmid=25306898}}</ref>
-* Chromosomal Rearrangements (Gene Fusions)
-* Individual Region Genomic Gain/Loss/LOH
-* Characteristic Chromosomal Patterns
-* Gene Mutations (SNV/INDEL)}}</blockquote>
-*There are no FDA approved targeted therapies for T-LGL
-*STAT3 mutations can be used to follow-up, in response to treatment<ref name=":4" />
-**Take caution as STAT mutations are not specific to T-LGL and can be seen in other T-cell lymphomas
-*STAT3 mutation, Y640F, has a predicted response to initial therapy with methotrexate<ref>Loughran TP, Zickl L, Olson TL, Wang V, Zhang D, Rajala HL, Hasanali Z, Bennett JM, Lazarus HM, Litzow MR, Evens AM. Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia. 2015 Apr;29(4):886-94.</ref>
-*Bortezomib is considered due to NF-κB  constitutive activity in T-LGL leukemia<ref>Mishra A, Liu S, Sams GH, Curphey DP, Santhanam R, Rush LJ, Schaefer D, Falkenberg LG, Sullivan L, Jaroncyk L, Yang X. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer cell. 2012 Nov 13;22(5):645-55.</ref>
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Individual Region Genomic Gain / Loss / LOH==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.'') </span>
+STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<ref name=":13">{{Cite journal|last=Yabe|first=Mariko|last2=Medeiros|first2=L. Jeffrey|last3=Wang|first3=Sa A.|last4=Tang|first4=Guilin|last5=Bueso-Ramos|first5=Carlos E.|last6=Jorgensen|first6=Jeffrey L.|last7=Bhagat|first7=Govind|last8=Chen|first8=Weina|last9=Li|first9=Shaoying|date=2017-01|title=Distinguishing Between Hepatosplenic T-cell Lymphoma and γδ T-cell Large Granular Lymphocytic Leukemia: A Clinicopathologic, Immunophenotypic, and Molecular Analysis|url=https://journals.lww.com/00000478-201701000-00010|journal=American Journal of Surgical Pathology|language=en|volume=41|issue=1|pages=82–93|doi=10.1097/PAS.0000000000000743|issn=0147-5185}}</ref>
-{| class="wikitable sortable"
+% of patients with STAT3 mutations, had multiple mutations in the STAT3 gene, solely in cytotoxic CD8+ or NK cells.<ref name=":4">Rajala HL, Olson T, Clemente MJ, Lagström S, Ellonen P, Lundan T, Hamm DE, Zaman SA, Marti JM, Andersson EI, Jerez A. The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia. haematologica. 2015 Jan 1;100(1):91-9.</ref>
 |-
-!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
+|STAT5B <ref name=":9" /><br />
-!Diagnostic Significance (Yes, No or Unknown)
+|Gain of function src-like homologue 2 (SH2) domain of STAT5.
-!Prognostic Significance (Yes, No or Unknown)
+Mutations include<ref name=":14">{{Cite journal|last=Bhattacharya|first=Dipabarna|last2=Teramo|first2=Antonella|last3=Gasparini|first3=Vanessa Rebecca|last4=Huuhtanen|first4=Jani|last5=Kim|first5=Daehong|last6=Theodoropoulos|first6=Jason|last7=Schiavoni|first7=Gianluca|last8=Barilà|first8=Gregorio|last9=Vicenzetto|first9=Cristina|date=2022-02-24|title=Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia|url=https://www.nature.com/articles/s41408-022-00630-8|journal=Blood Cancer Journal|language=en|volume=12|issue=2|pages=31|doi=10.1038/s41408-022-00630-8|issn=2044-5385|pmc=8873566|pmid=35210405}}</ref>:
-!Therapeutic Significance (Yes, No or Unknown)
-!Notes
-|-
-|<span class="blue-text">EXAMPLE:</span>
+N642H
-|<span class="blue-text">EXAMPLE:</span> Loss
-|<span class="blue-text">EXAMPLE:</span>
-chr7:1- 159,335,973 [hg38]
+Y665F
-|<span class="blue-text">EXAMPLE:</span>
-chr7
+Q706L
-|Yes
-|Yes
-|No
-|<span class="blue-text">EXAMPLE:</span>
-Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
+S715F
-|-
-|<span class="blue-text">EXAMPLE:</span>
+T628S
-|<span class="blue-text">EXAMPLE:</span> Gain
-|<span class="blue-text">EXAMPLE:</span>
-chr8:1-145,138,636 [hg38]
+P685R
-|<span class="blue-text">EXAMPLE:</span>
-chr8
+V712E mutation of STAT5B is in the transactivation domain<ref name=":14" />
-|No
-|No
-|No
-|<span class="blue-text">EXAMPLE:</span>
-Common recurrent secondary finding for t(8;21) (add reference).
+Mutations in the coiled-coil domain: CCD, Q220H <ref name=":14" />
-|}
-<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
+Mutations in the DNA binding domain: DBD, E433G/K <ref name=":14" />
-*No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in few cases<ref name=":9" />
+Mutations in the inter-domain region: P702A <ref name=":14" />
+|Other <ref>{{Cite journal|title=STAT5B signal transducer and activator of transcription 5B [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/6777}}</ref>
+|Rare <ref name=":3" />
+|D,P,T
+|WHO, NCCN
+|N642H mutation (associated with more aggressive disease)<ref>{{Cite journal|last=Rajala|first=Hanna L. M.|last2=Eldfors|first2=Samuli|last3=Kuusanmäki|first3=Heikki|last4=van Adrichem|first4=Arjan J.|last5=Olson|first5=Thomas|last6=Lagström|first6=Sonja|last7=Andersson|first7=Emma I.|last8=Jerez|first8=Andres|last9=Clemente|first9=Michael J.|date=2013-05-30|title=Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia|url=https://ashpublications.org/blood/article/121/22/4541/31378/Discovery-of-somatic-STAT5b-mutations-in-large|journal=Blood|language=en|volume=121|issue=22|pages=4541–4550|doi=10.1182/blood-2012-12-474577|issn=0006-4971|pmc=3668487|pmid=23596048}}</ref><ref name=":15">{{Cite journal|last=Rajala|first=Hanna L. M.|last2=Porkka|first2=Kimmo|last3=Maciejewski|first3=Jaroslaw P.|last4=Loughran|first4=Thomas P.|last5=Mustjoki|first5=Satu|date=2014-05-01|title=Uncovering the pathogenesis of large granular lymphocytic leukemia—novel STAT3 and STAT5b mutations|url=https://www.tandfonline.com/doi/full/10.3109/07853890.2014.882105|journal=Annals of Medicine|language=en|volume=46|issue=3|pages=114–122|doi=10.3109/07853890.2014.882105|issn=0785-3890}}</ref><br />
+Clones can acquire multiple STAT5B mutations <ref name=":14" />
-<blockquote class="blockedit">
+STAT5B mutations can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<ref name=":13" />
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Characteristic Chromosomal Patterns==
-Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.'')</span>
+N642H mutation is associated with CD3+/CD56+ phenotype<ref name=":15" />
-{| class="wikitable sortable"
+STAT5B mutations are more common in CD4+ T-LGLL than in CD8+ T-LGLL <ref name=":14" /><ref>{{Cite journal|last=Andersson|first=Emma I.|last2=Tanahashi|first2=Takahiro|last3=Sekiguchi|first3=Nodoka|last4=Gasparini|first4=Vanessa Rebecca|last5=Bortoluzzi|first5=Sabrina|last6=Kawakami|first6=Toru|last7=Matsuda|first7=Kazuyuki|last8=Mitsui|first8=Takeki|last9=Eldfors|first9=Samuli|date=2016-11-17|title=High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia|url=https://ashpublications.org/blood/article/128/20/2465/35603/High-incidence-of-activating-STAT5B-mutations-in|journal=Blood|language=en|volume=128|issue=20|pages=2465–2468|doi=10.1182/blood-2016-06-724856|issn=0006-4971|pmc=5114490|pmid=27697773}}</ref>
 |-
-!Chromosomal Pattern
+|TNFAIP3 <ref name=":9" />
-!Diagnostic Significance (Yes, No or Unknown)
+|Loss of function
-!Prognostic Significance (Yes, No or Unknown)
+Somatic mutations:
-!Therapeutic Significance (Yes, No or Unknown)
-!Notes
-|-
-|<span class="blue-text">EXAMPLE:</span>
-Co-deletion of 1p and 18q
+Y353X
-|Yes
-|No
-|No
-|<span class="blue-text">EXAMPLE:</span>
-See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
+K354K
-|}
-<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
+Q741
-*No characteristic chromosomal aberrations have been identified
+E630X
-*Unique cytogenetic findings include:  <small>(reported in one case report of γδ variant T-cell LGL)</small><ref name=":3" />
-**Interstitial deletion of 3p21.31, monosomy X, trisomy 5, monosomy 21, and CN‐LOH located at 17q<ref name=":3">Zhang L, Ramchandren R, Papenhausen P, Loughran TP, Sokol L. Transformed aggressive γδ‐variant T‐cell large granular lymphocytic leukemia with acquired copy neutral loss of heterozygosity at 17q11. 2q25. 3 and additional aberrations. European journal of haematology. 2014 Sep;93(3):260-4.</ref>
-***
-<blockquote class="blockedit">
+A717T
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Gene Mutations (SNV / INDEL)==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.'') </span>
+F127C <ref>{{Cite journal|last=Johansson|first=Patricia|last2=Bergmann|first2=Anke|last3=Rahmann|first3=Sven|last4=Wohlers|first4=Inken|last5=Scholtysik|first5=René|last6=Przekopowitz|first6=Martina|last7=Seifert|first7=Marc|last8=Tschurtschenthaler|first8=Gertraud|last9=Webersinke|first9=Gerald|date=2016-01-01|title=Recurrent alterations of TNFAIP 3 (A20) in T-cell large granular lymphocytic leukemia: A20 mutations in T-LGL|url=https://onlinelibrary.wiley.com/doi/10.1002/ijc.29697|journal=International Journal of Cancer|language=en|volume=138|issue=1|pages=121–124|doi=10.1002/ijc.29697}}</ref>
+|Other <ref>{{Cite journal|title=TNFAIP3 TNF alpha induced protein 3 [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/7128|language=en}}</ref>
+|Recurrent <ref name=":16">{{Cite journal|last=Upadhyayula|first=Bhanu Surabi|last2=Saglimbeni|first2=Grace S.|last3=Gobel|first3=Edie|last4=Gobel|first4=Abbi|last5=Morris|first5=Tyson J.|last6=Surendra|first6=Akaash|last7=Hsia|first7=Beau|last8=Sood|first8=Akshat|last9=Tauseef|first9=Abubakar|date=2026-01|title=Mutational Spectrum of T-Cell Large Granular Lymphocytic Leukemia: Insights From the AACR Project GENIE Consortium|url=http://cgp.iiarjournals.org/lookup/doi/10.21873/cgp.20566|journal=Cancer Genomics - Proteomics|language=en|volume=23|issue=1|pages=135–143|doi=10.21873/cgp.20566|issn=1109-6535|pmc=12758657|pmid=41482347}}</ref>
+|P,T
+|WHO
+|TNFAIP 3 mutation has been correlated with increased overall survival <ref>{{Cite journal|last=Chen|first=Cunte|last2=Chen|first2=Zheng|last3=Huang|first3=Ling|last4=Zhou|first4=Lingling|last5=Zhu|first5=Lihua|last6=Liu|first6=Sichu|last7=Luo|first7=Gengxin|last8=Li|first8=Wenyu|last9=Zeng|first9=Chengwu|date=2021-09-15|title=TNFAIP3 mutation may be associated with favorable overall survival for patients with T-cell lymphoma|url=https://doi.org/10.1186/s12935-021-02191-5|journal=Cancer Cell International|language=en|volume=21|issue=1|pages=490|doi=10.1186/s12935-021-02191-5|issn=1475-2867|pmc=8444556|pmid=34526012}}</ref>
+TNFAIP3 itself is a NF‐κB target gene<ref>{{Cite journal|last=Zhang|first=Ranran|last2=Shah|first2=Mithun Vinod|last3=Yang|first3=Jun|last4=Nyland|first4=Susan B.|last5=Liu|first5=Xin|last6=Yun|first6=Jong K.|last7=Albert|first7=Réka|last8=Loughran|first8=Thomas P.|date=2008-10-21|title=Network model of survival signaling in large granular lymphocyte leukemia|url=https://www.pnas.org/doi/full/10.1073/pnas.0806447105|journal=Proceedings of the National Academy of Sciences|volume=105|issue=42|pages=16308–16313|doi=10.1073/pnas.0806447105|pmc=2571012|pmid=18852469}}</ref>
-{| class="wikitable sortable"
+In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (''p''  = 0.004)<ref name=":11" />
+|-
+|TET2 <ref name=":9" />
+|Loss of function <ref name=":0">{{Cite journal|last=Cheon|first=HeeJin|last2=Xing|first2=Jeffrey C.|last3=Moosic|first3=Katharine B.|last4=Ung|first4=Johnson|last5=Chan|first5=Vivian W.|last6=Chung|first6=David S.|last7=Toro|first7=Mariella F.|last8=Elghawy|first8=Omar|last9=Wang|first9=John S.|date=2022-05-19|title=Genomic landscape of TCRαβ and TCRγδ T-large granular lymphocyte leukemia|url=https://ashpublications.org/blood/article/139/20/3058/483429/Genomic-landscape-of-TCR-and-TCR-T-large-granular|journal=Blood|language=en|volume=139|issue=20|pages=3058–3072|doi=10.1182/blood.2021013164|issn=0006-4971|pmc=9121841|pmid=35015834}}</ref>
+|Other <ref>{{Cite journal|title=TET2 tet methylcytosine dioxygenase 2 [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/54790}}</ref>
+|Common <ref name=":16" />
+|N/A
+|WHO
+|Found to be the most prevalent mutation in myeloid neoplasm or myeloid clonal hematopoiesis coexisting with T-LGLL <ref name=":1">{{Cite journal|last=Kawashima|first=Naomi|last2=Gurnari|first2=Carmelo|last3=Bravo-Perez|first3=Carlos|last4=Kubota|first4=Yasuo|last5=Pagliuca|first5=Simona|last6=Guarnera|first6=Luca|last7=Williams|first7=Nakisha D.|last8=Durmaz|first8=Arda|last9=Ahmed|first9=Arooj|date=2025-02|title=Clonal hematopoiesis in large granular lymphocytic leukemia|url=https://www.nature.com/articles/s41375-024-02460-y|journal=Leukemia|language=en|volume=39|issue=2|pages=451–459|doi=10.1038/s41375-024-02460-y|issn=1476-5551}}</ref>
+|-
+|BCL11B <ref name=":9" />
+|Missense H126R<ref name=":17">{{Cite journal|last=Andersson|first=E. I.|last2=Rajala|first2=H. L. M.|last3=Eldfors|first3=S.|last4=Ellonen|first4=P.|last5=Olson|first5=T.|last6=Jerez|first6=A.|last7=Clemente|first7=M. J.|last8=Kallioniemi|first8=O.|last9=Porkka|first9=K.|date=2013-12|title=Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation|url=https://www.nature.com/articles/bcj201365|journal=Blood Cancer Journal|language=en|volume=3|issue=12|pages=e168–e168|doi=10.1038/bcj.2013.65|issn=2044-5385|pmc=3877422|pmid=24317090}}</ref>
+|Other<ref>{{Cite journal|title=BCL11 transcription factor B|url=https://www.ncbi.nlm.nih.gov/datasets/gene/64919/|language=en}}</ref>
+|Rare<ref name=":17" />
+|N/A
+|WHO
+|BCL11B is required for T-cell survival and overexpression could effectively increase T-cell activation and proliferation.<ref name=":17" />
+|-
+|FLT3<ref name=":9" />
+|A high-impact Asp228Gly variant on JAK STAT has been demonstrated <ref name=":18">{{Cite journal|last=Coppe|first=A|last2=Andersson|first2=E I|last3=Binatti|first3=A|last4=Gasparini|first4=V R|last5=Bortoluzzi|first5=S|last6=Clemente|first6=M|last7=Herling|first7=M|last8=Maciejewski|first8=J|last9=Mustjoki|first9=S|date=2017-05|title=Genomic landscape characterization of large granular lymphocyte leukemia with a systems genetics approach|url=https://www.nature.com/articles/leu201749|journal=Leukemia|language=en|volume=31|issue=5|pages=1243–1246|doi=10.1038/leu.2017.49|issn=0887-6924|pmc=5419584|pmid=28167832}}</ref>
+|Other<ref>{{Cite journal|title=fms related receptor tyrosine kinase 3|url=https://www.ncbi.nlm.nih.gov/datasets/gene/2322/|language=en}}</ref>
+|Rare<ref name=":18" />
+|N/A
+|WHO
+|Connects STAT to the MAPK-Ras-ERK pathway and to IL-15<ref name=":18" />
 |-
-!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
+|PTPN23<ref name=":9" />
-!'''Diagnostic Significance (Yes, No or Unknown)'''
+|R641Q<ref name=":19">{{Cite journal|last=Andersson|first=Emma I.|last2=Tanahashi|first2=Takahiro|last3=Sekiguchi|first3=Nodoka|last4=Gasparini|first4=Vanessa Rebecca|last5=Bortoluzzi|first5=Sabrina|last6=Kawakami|first6=Toru|last7=Matsuda|first7=Kazuyuki|last8=Mitsui|first8=Takeki|last9=Eldfors|first9=Samuli|date=2016-11-17|title=High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia|url=https://ashpublications.org/blood/article/128/20/2465/35603/High-incidence-of-activating-STAT5B-mutations-in|journal=Blood|language=en|volume=128|issue=20|pages=2465–2468|doi=10.1182/blood-2016-06-724856|issn=0006-4971|pmc=5114490|pmid=27697773}}</ref>
-!Prognostic Significance (Yes, No or Unknown)
+|Other<ref>{{Cite journal|title=protein tyrosine phosphatase non-receptor type 23|url=https://www.ncbi.nlm.nih.gov/datasets/gene/25930/|language=en}}</ref>
-!Therapeutic Significance (Yes, No or Unknown)
+|Rare<ref name=":19" />
-!Notes
+|N/A
+|WHO
+|Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation<ref name=":19" />
 |-
-|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations
+|KMT2D<ref name=":0" />
+|Loss of function<ref name=":0" />
+|Other<ref>{{Cite journal|title=KMT2D lysine methyltransferase 2D [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/8085}}</ref>
+|Recurrent<ref name=":16" />
+|N/A
+|None
+|KMT2D has been linked to lymphomagenesis.<ref name=":18" />
-<span class="blue-text">EXAMPLE:</span>
-EGFR; Exon 20 mutations
+KMT2D has been how to exhibit significant co-occurrence with STAT3 mutation<ref name=":0" />
+|-
+|TRAF3 <ref name=":1" />
+|c.650A>T p.E217V<ref name=":1" />
+|Other<ref>{{Cite journal|title=TRAF3 TNF receptor associated factor 3 [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/7187}}</ref>
+|Rare<ref name=":1" />
+|N/A
+|None
+|Mutated putative driver<ref name=":1" />
+|-
+|CLIP3<ref name=":1" />
+|c.908A>T p.D303V
-<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
-|<span class="blue-text">EXAMPLE:</span> TSG
-|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
-<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
-|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
-|<span class="blue-text">EXAMPLE:</span> EGFR amplification
-|
-|
-|
-|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
-<br />
-|}
-Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
+c.917A>T p.K306M<ref name=":1" />
+|Other<ref>{{Cite journal|title=TRAF3 TNF receptor associated factor 3 [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/7187}}</ref>
+|Rare<ref name=":1" />
+|N/A
+|None
+|Mutated putative driver<ref name=":1" />
+|-
+|FBXW2<ref name=":1" />
+|c.683C>G p.A228G <ref name=":1" />
+|Other<ref>{{Cite journal|title=F-box and WD repeat domain containing 2|url=https://www.ncbi.nlm.nih.gov/datasets/gene/26190/|language=en}}</ref>
+|Rare<ref name=":1" />
+|N/A
+|None
+|Mutated putative driver<ref name=":1" />
+|-
+|CREBBP<ref name=":1" />
+|c.1178A>G p.N393S
-<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>
-Somatic activating STAT3 and STAT5b mutations are the most common SNVs in T-LGL.
+c.4306T>C p.C1436R<ref name=":1" />
+|Other<ref>{{Cite journal|title=CREBBP CREB binding lysine acetyltransferase [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/1387}}</ref>
-{| class="wikitable sortable"
+|Rare<ref name=":1" />
-|-
+|N/A
-!Gene*!!Mutation!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence
+|None
-!Additional information
+|Mutated putative driver <ref name=":1" />
 |-
-|STAT3||
+|CCL2 <ref name=":2">{{Cite journal|last=Mizuno|first=Yuga|last2=Kawakami|first2=Toru|last3=Higano|first3=Daigo|last4=Miyairi|first4=Shotaro|last5=Asakura|first5=Ami|last6=Kawakami|first6=Fumihiro|last7=Sato|first7=Keijiro|last8=Matsuzawa|first8=Shuji|last9=Nishina|first9=Sayaka|date=2024-05-30|title=CCL22 mutations in large granular lymphocytic leukemia|url=https://haematologica.org/article/view/haematol.2024.285404|journal=Haematologica|doi=10.3324/haematol.2024.285404|issn=1592-8721|pmc=11367240|pmid=38813714}}</ref>
-*Src-like homologue 2 (SH2) domain of STAT3
+|SNV, somatic Mutation
-*Most frequently affecting codons Y640 or D661<ref name=":0" />
-**Also affecting:
-***N647I<ref name=":6">Johansson P, Bergmann A, Rahmann S, Wohlers I, Scholtysik R, Przekopowitz M, Seifert M, Tschurtschenthaler G, Webersinke G, Jäger U, Siebert R. Recurrent alterations of TNFAIP 3 (A 20) in T‐cell large granular lymphocytic leukemia. International journal of cancer. 2016 Jan 1;138(1):121-4.</ref>
-***K658S<ref name=":6" />
-*Causing constitutive phosphorylation of the mutated proteins, and increased the transcriptional activity of STAT3 in vitro<ref name=":1">Jerez A, Clemente MJ, Makishima H, Koskela H, LeBlanc F, Peng Ng K, Olson T, Przychodzen B, Afable M, Gomez-Segui I, Guinta K. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood, The Journal of the American Society of Hematology. 2012 Oct 11;120(15):3048-57.</ref><ref name=":2">Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, Lagström S, Clemente MJ, Olson T, Jalkanen SE, Majumder MM. Somatic STAT3 mutations in large granular lymphocytic leukemia. New England Journal of Medicine. 2012 May 17;366(20):1905-13.</ref>
+P46R<ref name=":2" />
-|'''GOF'''||40-70%<ref name=":2" />
+|Other<ref>{{Cite journal|title=C-C motif chemokine ligand 2|url=https://www.ncbi.nlm.nih.gov/datasets/gene/6347/|language=en}}</ref>
-|
+|Rare<ref name=":2" />
-*17% of patients with STAT3 mutations, had multiple mutations in the STAT3 gene, solely in cytotoxic CD8+ or NK cells.<ref name=":4">Rajala HL, Olson T, Clemente MJ, Lagström S, Ellonen P, Lundan T, Hamm DE, Zaman SA, Marti JM, Andersson EI, Jerez A. The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia. haematologica. 2015 Jan 1;100(1):91-9.</ref>
+|N/A
-*Take caution as STAT3 mutation can also be seen in other T-cell lymphomas including [[HAEM5:Hepatosplenic T-cell lymphoma|hepatosplenic T-cell lymphoma]]<ref name=":5">Yabe M, Medeiros LJ, Wang SA, Tang G, Bueso-Ramos CE, Jorgensen JL, Bhagat G, Chen W, Li S, Young KH, Miranda RN. Distinguishing between hepatosplenic T-cell lymphoma and γδ T-cell large granular lymphocytic leukemia. The American journal of surgical pathology. 2017 Jan 1;41(1):82-93.</ref>
+|None
-|-
+|CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL<ref name=":2" />
-|STAT5B
+CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL<ref name=":2" />
-|
+|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
-*Src-like homologue 2 (SH2) domain of STAT5
-*Including: N642H mutation (associated with more aggressive disease)<ref name=":7" /><ref name=":8">Rajala HL, Porkka K, Maciejewski JP, Loughran Jr TP, Mustjoki S. Uncovering the pathogenesis of large granular lymphocytic leukemia—novel STAT3 and STAT5b mutations. Annals of Medicine. 2014 May 1;46(3):114-22.</ref>
-*Causing constitutive phosphorylation of the mutated proteins, and increased the transcriptional activity of STAT5B in vitro<ref name=":1" /><ref name=":2" />
+<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote><br />
-*
+<blockquote class="blockedit"><center><span style="color:Maroon">'''End of V4 Section'''</span>
-|'''GOF'''
-|2%<ref name=":7">Rajala HL, Eldfors S, Kuusanmäki H, Van Adrichem AJ, Olson T, Lagström S, Andersson EI, Jerez A, Clemente MJ, Yan Y, Zhang D. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood, The Journal of the American Society of Hematology. 2013 May 30;121(22):4541-50.</ref>
-|
-*Take caution as STAT5B mutations can also be seen in other T-cell lymphomas including [[HAEM5:Hepatosplenic T-cell lymphoma|hepatosplenic T-cell lymphoma]]<ref name=":5" />
-*N642H mutation is associated with CD3+/CD56+ phenotype<ref name=":8" />
-|-
-|TNFAIP3
-|
-*Somatic mutations<ref name=":6" />
-**Y353X
-**K354K
-**Q741Q
-**E630X
-**A717T
-**F127C
-|'''LOF''' (Nonsense mutations)<ref name=":6" />
-|Identified in 3/39 patients<ref name=":6" />
-|
-*In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (''p''  = 0.004)<ref name=":6" />
-*TNFAIP3 itself is a NF‐κB target gene<ref>Zhang R, Shah MV, Yang J, Nyland SB, Liu X, Yun JK, Albert R, Loughran TP. Network model of survival signaling in large granular lymphocyte leukemia. Proceedings of the National Academy of Sciences. 2008 Oct 21;105(42):16308-13.</ref>
-|}
-<nowiki>*</nowiki>More comprehensive listing of specific mutations in these genes can be found elsewhere ([https://cancer.sanger.ac.uk/cosmic COSMIC], [https://www.cbioportal.org/ cBioPortal])
-<br />
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
 ----
 </blockquote>
 ==Epigenomic Alterations==
-* Epigenetic inactivation of JAK/STAT pathway inhibitors
+*Epigenetic inactivation of JAK/STAT pathway inhibitors
-** SOCS3 has a crucial role in regulating STAT3 activation<ref name=":10">{{Cite journal|last=Teramo|first=Antonella|last2=Gattazzo|first2=Cristina|last3=Passeri|first3=Francesca|last4=Lico|first4=Albana|last5=Tasca|first5=Giulia|last6=Cabrelle|first6=Anna|last7=Martini|first7=Veronica|last8=Frezzato|first8=Federica|last9=Trimarco|first9=Valentina|date=2013-05-09|title=Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23515927|journal=Blood|volume=121|issue=19|pages=3843–3854, S1|doi=10.1182/blood-2012-07-441378|issn=1528-0020|pmid=23515927}}</ref>
+**SOCS3 has a crucial role in regulating STAT3 activation<ref name=":10">{{Cite journal|last=Teramo|first=Antonella|last2=Gattazzo|first2=Cristina|last3=Passeri|first3=Francesca|last4=Lico|first4=Albana|last5=Tasca|first5=Giulia|last6=Cabrelle|first6=Anna|last7=Martini|first7=Veronica|last8=Frezzato|first8=Federica|last9=Trimarco|first9=Valentina|date=2013-05-09|title=Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23515927|journal=Blood|volume=121|issue=19|pages=3843–3854, S1|doi=10.1182/blood-2012-07-441378|issn=1528-0020|pmid=23515927}}</ref>
-** An epigenetic inhibition mechanism to SOCS3 gene is hypothesized<ref name=":10" />
+**An epigenetic inhibition mechanism to SOCS3 gene is hypothesized<ref name=":10" />
-** KIR3DL1 has been shown to be down-modulated by hypermethylation of the promoter<ref name=":10" />
+**KIR3DL1 has been shown to be down-modulated by hypermethylation of the promoter<ref name=":10" />
+**Mutations in KMT2D and TET2 have been found to significantly co-occur with STAT3 mutations<ref name=":0" />
 <br />
@@ Line 385: / Line 355: @@
 ==Genes and Main Pathways Involved==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
+<span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
 {| class="wikitable sortable"
 |-
 !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 |-
-|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
+|JAK/STAT<ref name=":3" />
-|<span class="blue-text">EXAMPLE:</span> MAPK signaling
+|Constitutive activation
-|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
+|Dysregulation of apoptosis
+|-
+|NK-kB<ref name=":3" />
+|Pathway activation
+|Preventing apoptosis
+|-
+|FAS and FASL<ref name=":3" />
+|Resistance to FAS mediated apoptosis
+|Activation of pro-survival pathways which is postulated to lead to neutropenia
 |-
-|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
+|RAS/RAF1/MEK1/ERK<ref name=":3" />
-|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
+|Overactive RAS
-|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
+|Constitutive activation of RAS and ERK
 |-
-|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
+|PI3K/AKT<ref name=":3" />
-|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
+|Dysregulation
-|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
+|Apoptosis inhibition
 |}
-<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
+<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
-*JAK/STAT<ref name=":9" />
+**
-**Constitutive activation
-*NK-κB<ref name=":9" />
-**Activation of this pathway
-**Preventing apoptosis
-*T-LGL's express high levels of FAS and FASL<ref name=":9">Lamy T, Moignet A, Loughran TP. LGL leukemia: from pathogenesis to treatment. Blood. 2017 Mar 2;129(9):1082-94.</ref>
-**Resistant to FAS mediated apoptosis
-**Leading to activation of prosurvival pathways
-**Postulated to lead to neutropenia seen in these patients.
-*RAS/RAF1/MEK1/ERK <ref name=":9" />
-**Overactive RAS
-**Constitutive activation of RAS and ERK
-*PI3K/AKT<ref name=":9" />
-**Dysregulation
-**Contributing to apoptosis inhibition
 <blockquote class="blockedit">
@@ Line 427: / Line 391: @@
 ==Genetic Diagnostic Testing Methods==
 *Morphologic assessment, flow cytometry and immunohistochemistry
 *PCR to assess for clonality, T-cell receptor (TCR) gene rearrangements
-**TCR gamma (TCRG) gene is rearranged in all cases, regardless of the type of TCR expressed, thus proves clonality<ref name=":0" />
+** TCR gamma (TCRG) gene is rearranged in all cases, regardless of the type of TCR expressed, thus proves clonality<ref name=":9" />
-***Can be helpful in differentiating a reactive lymphocytosis from clonal T-LGL's
+** Can be helpful in differentiating a reactive lymphocytosis from clonal T-LGL's
-**NK LGL proliferations do not express TCR, making assessment of clonality difficult<ref name=":9" />
+*** NK LGL proliferations do not express TCR, making assessment of clonality difficult<ref name=":3" />
-***Expression of activating isoforms of killer immunoglobulin-like receptors (KIR) can be used as a surrogate marker of clonality in NK LGL<ref name=":9" />
+*** Expression of activating isoforms of killer immunoglobulin-like receptors (KIR) can be used as a surrogate marker of clonality in NK LGL<ref name=":3" />
+* Myeloid neoplasms may present with clonal large granular lymphocyte expansion with STAT3/STAT5B mutations. Next generation sequencing can be diagnostically useful in these cases<ref>{{Cite journal|last=Kavesh|first=Mark|last2=Mohebnasab|first2=Maedeh|last3=Angel|first3=Marcela Riveros|last4=Xie|first4=Wei|last5=Raess|first5=Philipp W.|last6=Cui|first6=Wei|last7=Press|first7=Richard D.|last8=Yang|first8=Guang|last9=Li|first9=Peng|date=2023-01-10|title=Distinguishing STAT3/STAT5B -mutated large granular lymphocyte leukemia from myeloid neoplasms by genetic profiling|url=https://ashpublications.org/bloodadvances/article/7/1/40/486140/Distinguishing-STAT3-STAT5B-mutated-large-granular|journal=Blood Advances|language=en|volume=7|issue=1|pages=40–45|doi=10.1182/bloodadvances.2022008192|issn=2473-9529}}</ref>
 ==Familial Forms==
@@ Line 440: / Line 405: @@
 ==Additional Information==
-*N/A
+*PI3K-Akt has been found to be upregulated in KLRG1<sup>-</sup> CD8<sup>+</sup> T-LGLL. Studies are being conducted to examine treatment with linperlisib.<ref>{{Cite journal|last=Zhang|first=Lele|last2=Qiu|first2=Chen|last3=Li|first3=Ruonan|last4=Shen|first4=Yucan|last5=Tian|first5=Linzhu|last6=Chang|first6=Hong|last7=Liang|first7=Qian|last8=Pan|first8=Hong|last9=Gao|first9=Zhen|date=2025-04|title=KLRG1 re-defines a leukemic clone of CD8 effector T cells sensitive to PI3K inhibitor in T cell large granular lymphocytic leukemia|url=https://linkinghub.elsevier.com/retrieve/pii/S2666379125001090|journal=Cell Reports Medicine|language=en|volume=6|issue=4|pages=102036|doi=10.1016/j.xcrm.2025.102036|pmc=12047471|pmid=40147444}}</ref>
+*Myleoid clonal hematopoiesis is associated with the presence of cytopenia in LGLL<ref name=":1" />
 ==Links==
@@ Line 447: / Line 413: @@
 ==References==
-(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
+(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
-'''
+<br />
 ==Notes==
-<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
+<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
+Prior Author(s):
 <nowiki>*</nowiki>''Citation of this Page'': “T-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:T-large_granular_lymphocytic_leukaemia</nowiki>.
@@ Line 461: / Line 431: @@
 *[[HAEM4:Mature T- and NK-cell Neoplasms|Mature T- and NK-cell Neoplasm]]
-[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases T]]
+[[Category:HAEM5]]
+[[Category:DISEASE]]
+[[Category:Diseases T]]

HAEM5:T-large granular lymphocytic leukaemia: Difference between revisions

Latest revision as of 20:10, 16 January 2026

Primary Author(s)*

WHO Classification of Disease

Related Terminology

Gene Rearrangements

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal or Other Global Mutational Patterns

Gene Mutations (SNV/INDEL)

Epigenomic Alterations

Genes and Main Pathways Involved

Genetic Diagnostic Testing Methods

Familial Forms

Additional Information

Links

References

Notes

Other Sections

Navigation menu

Search