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

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|<span class="blue-text">EXAMPLE:</span> Common (CML)
|N/A
|<span class="blue-text">EXAMPLE:</span> D, P, T
|N/A
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
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|<span class="blue-text">EXAMPLE:</span>
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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). BCR::ABL1 is generally favorable in CML (add reference).
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*No known chromosomal rearrangements
*


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* Gene Mutations (SNV/INDEL)}}</blockquote>
* 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>


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==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==


 
No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in a few cases.<sup>[7]</sup> <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>
Put your text here and fill in the table <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>
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
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|<span class="blue-text">EXAMPLE:</span>
|N/A
7
|N/A
|<span class="blue-text">EXAMPLE:</span> Loss
|N/A
|<span class="blue-text">EXAMPLE:</span>
|N/A
chr7
|N/A
|<span class="blue-text">EXAMPLE:</span>
|N/A
Unknown
|N/A
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> 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 references).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
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|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
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|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
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*No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in few cases<ref name=":9" />
*


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Put your text here and fill in the table <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>
 
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.
 
<sup>[8]</sup> <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>
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
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|<span class="blue-text">EXAMPLE:</span>
|N/A
Co-deletion of 1p and 18q
|N/A
|<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).
|N/A
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|N/A
|<span class="blue-text">EXAMPLE:</span> D, P
|N/A
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|N/A
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|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
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|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
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*No characteristic chromosomal aberrations have been identified
*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>
***
***


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==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==


 
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>
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 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>
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|''STAT3'' <sup>[1]</sup>
|Gain of function in src-like homologue 2 (SH2) domain of STAT 3, frequently affecting codons Y640 or D661<sup>[1].</sup> Codons N647I<sup>[9]</sup>,K658S<sup>[9]</sup>, and K658F<sup>[22]</sup> are also affected
|Other <sup>[31]</sup>
|Common <sup>[11]</sup>
|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<sup>[22]</sup>
 
 
STAT3 mutations are associated with a worse prognosis and reduced overall survival <sup>[1][23]</sup>
 
 
Patients with STAT 3 mutation required treatment more frequently when compared to patients with STAT3 wild type<sup>[18]</sup>
 
 
One prospective study showed a predictive response to methotrexate therapy in a small group of patients with STAT3 Y640F mutated genotype<sup>[25]</sup>
 
 
STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<sup>[12]</sup>
|-
|STAT5B <sup>[1]</sup> <br />
|Gain of function src-like homologue 2 (SH2) domain of STAT5.
Mutations include<sup>[19]</sup>:
N642H
Y665F
Q706L
S715F
T628S
P685R
 
V712E mutation of STAT5B is in the transactivation domain<sup>[19]</sup>
 
Mutations in the coiled-coil domain: CCD, Q220H <sup>[19]</sup>  
 
Mutations in the DNA binding domain: DBD, E433G/K <sup>[19]</sup>  
 
Mutations in the inter-domain region: P702A <sup>[19]</sup>
|Other <sup>[32]</sup>
|Common <sup>[20]</sup>
|D,P,T
|WHO, NCCN
|N642H mutation (associated with more aggressive disease)<sup>[13][14]</sup>
 
 
Clones can acquire multiple STAT5B mutations <sup>[19]</sup>
 
 
STAT5B mutations can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<sup>[12</sup>
 
 
N642H mutation is associated with CD3+/CD56+ phenotype<sup>[14]</sup>
 
 
STAT5B mutations are more common in CD4+ T-LGLL than in CD8+ T-LGLL <sup>[19][20]</sup>
|-
|TNFAIP3 <sup>[1]</sup>
|Loss of function
Somatic mutations:
 
Y353X


<br />
K354K
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
 
|<span class="blue-text">EXAMPLE:</span> Oncogene
Q741
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
 
|<span class="blue-text">EXAMPLE:</span> T
E630X
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
 
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
A717T
 
F127C <sup>[9]</sup>
|Other <sup>[33]</sup>  
|Recurrent <sup>[46]</sup>  
|P,T
|WHO
|TNFAIP 3 mutation has been correlated with increased overall survival <sup>[17]</sup>  
 
 
TNFAIP3 itself is a NF‐κB target gene<sup>[15]</sup>  
 
 
In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (''p''  = 0.004)<sup>[9]</sup>  
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|TET2 <sup>[1]</sup>  
<br />
|Loss of function <sup>[26]</sup>  
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|Other <sup>[34]</sup>  
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|Common <sup>[46]</sup>  
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|N/A
|<span class="blue-text">EXAMPLE:</span> P
|WHO
|
|Found to be the most prevalent mutation in myeloid neoplasm or myeloid clonal hematopoiesis coexisting with T-LGLL <sup>[30]</sup>  
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|BCL11B <sup>[1]</sup>
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|Missense H126R <sup>[43]</sup>
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Other <sup>[35]</sup>
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Rare <sup>[43]</sup>
|<span class="blue-text">EXAMPLE:</span> T
|N/A
|
|WHO
|
|BCL11B is required for T-cell survival and overexpression could effectively increase T-cell activation and proliferation. <sup>[43]</sup>
|-
|FLT3 <sup>[1]</sup>
|A high-impact Asp228Gly variant on JAK STAT has been demonstrated <sup>[44]</sup>  
|Other <sup>[36]</sup>
|Rare <sup>[44]</sup>
|N/A
|WHO
|Connects STAT to the MAPK-Ras-ERK pathway and to IL-15 <sup>[44]</sup>  
|-
|PTPN23 <sup>[1]</sup>
|R641Q <sup>[45]</sup>
|Other <sup>[37]</sup>
|Rare <sup>[45]</sup>
|N/A
|WHO
|Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation <sup>[45]</sup>  
|-
|KMT2D <sup>[26]</sup>
|Loss of function <sup>[26]</sup>
|Other <sup>[38]</sup>
|Recurrent <sup>[46]</sup>  
|N/A
|None
|KMT2D has been linked to lymphomagenesis. <sup>[44]</sup>  
 
 
KMT2D has been how to exhibit significant co-occurrence with STAT3 mutation <sup>[26]</sup>
|-
|-
|
|CLIP3 <sup>[30]</sup>
|
|
|
|

Revision as of 20:00, 14 January 2026

Haematolymphoid Tumours (WHO Classification, 5th ed.)

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.[7] (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.

[8] (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 [1] Gain of function in src-like homologue 2 (SH2) domain of STAT 3, frequently affecting codons Y640 or D661[1]. Codons N647I[9],K658S[9], and K658F[22] are also affected Other [31] Common [11] 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[22]


STAT3 mutations are associated with a worse prognosis and reduced overall survival [1][23]


Patients with STAT 3 mutation required treatment more frequently when compared to patients with STAT3 wild type[18]


One prospective study showed a predictive response to methotrexate therapy in a small group of patients with STAT3 Y640F mutated genotype[25]


STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma[12]

STAT5B [1]
Gain of function src-like homologue 2 (SH2) domain of STAT5.

Mutations include[19]: N642H Y665F Q706L S715F T628S P685R

V712E mutation of STAT5B is in the transactivation domain[19]

Mutations in the coiled-coil domain: CCD, Q220H [19]

Mutations in the DNA binding domain: DBD, E433G/K [19]

Mutations in the inter-domain region: P702A [19]

Other [32] Common [20] D,P,T WHO, NCCN N642H mutation (associated with more aggressive disease)[13][14]


Clones can acquire multiple STAT5B mutations [19]


STAT5B mutations can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma[12


N642H mutation is associated with CD3+/CD56+ phenotype[14]


STAT5B mutations are more common in CD4+ T-LGLL than in CD8+ T-LGLL [19][20]

TNFAIP3 [1] Loss of function

Somatic mutations:

Y353X

K354K

Q741

E630X

A717T

F127C [9]

Other [33] Recurrent [46] P,T WHO TNFAIP 3 mutation has been correlated with increased overall survival [17]


TNFAIP3 itself is a NF‐κB target gene[15]


In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (p  = 0.004)[9]

TET2 [1] Loss of function [26] Other [34] Common [46] N/A WHO Found to be the most prevalent mutation in myeloid neoplasm or myeloid clonal hematopoiesis coexisting with T-LGLL [30]
BCL11B [1] Missense H126R [43] Other [35] Rare [43] N/A WHO BCL11B is required for T-cell survival and overexpression could effectively increase T-cell activation and proliferation. [43]
FLT3 [1] A high-impact Asp228Gly variant on JAK STAT has been demonstrated [44] Other [36] Rare [44] N/A WHO Connects STAT to the MAPK-Ras-ERK pathway and to IL-15 [44]
PTPN23 [1] R641Q [45] Other [37] Rare [45] N/A WHO Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation [45]
KMT2D [26] Loss of function [26] Other [38] Recurrent [46] N/A None KMT2D has been linked to lymphomagenesis. [44]  


KMT2D has been how to exhibit significant co-occurrence with STAT3 mutation [26]

CLIP3 [30]

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.

Somatic activating STAT3 and STAT5b mutations are the most common SNVs in T-LGL.

Gene* Mutation Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence Additional information
STAT3
  • Src-like homologue 2 (SH2) domain of STAT3
  • Most frequently affecting codons Y640 or D661[1]
    • Also affecting:
  • Causing constitutive phosphorylation of the mutated proteins, and increased the transcriptional activity of STAT3 in vitro[3][4]
 GOF 40-70%[4]
  • 17% of patients with STAT3 mutations, had multiple mutations in the STAT3 gene, solely in cytotoxic CD8+ or NK cells.[5]
  • Take caution as STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma[6]
STAT5B
  • Src-like homologue 2 (SH2) domain of STAT5
  • Including: N642H mutation (associated with more aggressive disease)[7][8]
  • Causing constitutive phosphorylation of the mutated proteins, and increased the transcriptional activity of STAT5B in vitro[3][4]
 GOF 2%[7]
  • Take caution as STAT5B mutations can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma[6]
  • N642H mutation is associated with CD3+/CD56+ phenotype[8]
TNFAIP3
  • Somatic mutations[2]
    • Y353X
    • K354K
    • Q741Q
    • E630X
    • A717T
    • F127C
 LOF (Nonsense mutations)[2] Identified in 3/39 patients[2]
  • In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (p  = 0.004)[2]
  • TNFAIP3 itself is a NF‐κB target gene[9]

*More comprehensive listing of specific mutations in these genes can be found elsewhere (COSMIC, cBioPortal)

End of V4 Section

Epigenomic Alterations

  • Epigenetic inactivation of JAK/STAT pathway inhibitors
    • SOCS3 has a crucial role in regulating STAT3 activation[10]
    • An epigenetic inhibition mechanism to SOCS3 gene is hypothesized[10]
    • KIR3DL1 has been shown to be down-modulated by hypermethylation of the promoter[10]


Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations EXAMPLE: Histone modification, chromatin remodeling EXAMPLE: Abnormal gene expression program
editv4:Genes and Main Pathways Involved
The content below was from the old template. Please incorporate above.
  • JAK/STAT[11]
    • Constitutive activation
  • NK-κB[11]
    • Activation of this pathway
    • Preventing apoptosis
  • T-LGL's express high levels of FAS and FASL[11]
    • Resistant to FAS mediated apoptosis
    • Leading to activation of prosurvival pathways
    • Postulated to lead to neutropenia seen in these patients.
  • RAS/RAF1/MEK1/ERK [11]
    • Overactive RAS
    • Constitutive activation of RAS and ERK
  • PI3K/AKT[11]
    • Dysregulation
    • Contributing to apoptosis inhibition
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[1]
      • 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[11]
      • Expression of activating isoforms of killer immunoglobulin-like receptors (KIR) can be used as a surrogate marker of clonality in NK LGL[11]

Familial Forms

  • No known familiar forms as of yet.

Additional Information

  • N/A

Links

References

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  1. ↑ 1.0 1.1 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.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 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.
  3. ↑ 3.0 3.1 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.
  4. ↑ 4.0 4.1 4.2 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.
  5. ↑ 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.
  6. ↑ 6.0 6.1 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.
  7. ↑ 7.0 7.1 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.
  8. ↑ 8.0 8.1 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.
  9. ↑ 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.
  10. ↑ 10.0 10.1 10.2 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.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 Lamy T, Moignet A, Loughran TP. LGL leukemia: from pathogenesis to treatment. Blood. 2017 Mar 2;129(9):1082-94.


Notes

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*Citation of this Page: “T-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 01/14/2026, https://ccga.io/index.php/HAEM5:T-large_granular_lymphocytic_leukaemia.

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