View source for HAEM5:T-large granular lymphocytic leukaemia

{{DISPLAYTITLE:T-large granular lymphocytic leukaemia}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

{{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>

<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
*Nicolas LaScala, DO

==WHO Classification of Disease==

{| class="wikitable"
!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==

{| 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
|}

<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>

*

<blockquote class="blockedit">
<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:
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}</blockquote>

*

<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Individual Region Genomic Gain/Loss/LOH==

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 sortable"
|-
!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
|}

<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">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==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.<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"
|-
!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
|}

<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">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==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>
{| class="wikitable sortable"
|-
!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''<ref name=":9">{{Cite journal|title=BlueBooksOnline|url=https://tumourclassification.iarc.who.int/chapters/63}}</ref> 
|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 
|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>
|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>
|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<ref name=":12" /> 



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>
 



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>
 



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>
 



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>

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>
|-
|STAT5B <ref name=":9" /><br />
|Gain of function src-like homologue 2 (SH2) domain of STAT5. 
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>:  

N642H  

Y665F  

Q706L  

S715F  

T628S  

P685R 

V712E mutation of STAT5B is in the transactivation domain<ref name=":14" /> 

Mutations in the coiled-coil domain: CCD, Q220H <ref name=":14" /> 

Mutations in the DNA binding domain: DBD, E433G/K <ref name=":14" /> 

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" />

STAT5B mutations can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<ref name=":13" />

N642H mutation is associated with CD3+/CD56+ phenotype<ref name=":15" /> 

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>
|-
|TNFAIP3 <ref name=":9" />
|Loss of function 
Somatic mutations:

Y353X 

K354K 

Q741 

E630X 

A717T 

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> 

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" />
|-
|PTPN23<ref name=":9" />
|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>
|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>
|Rare<ref name=":19" />
|N/A 
|WHO
|Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation<ref name=":19" />
|-
|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" />  


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 



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 


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>
|Rare<ref name=":1" />
|N/A 
|None
|Mutated putative driver <ref name=":1" />
|-
|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>
|SNV, somatic Mutation  

P46R<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" />
|N/A 
|None
|CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL<ref name=":2" />
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.

<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>
----
</blockquote>
==Epigenomic Alterations==

*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>
**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" />
**Mutations in KMT2D and TET2 have been found to significantly co-occur with STAT3 mutations<ref name=":0" />

<br />

==Genes and Main Pathways Involved==

<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
|-
|JAK/STAT<ref name=":3" />
|Constitutive activation 
|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 
|-
|RAS/RAF1/MEK1/ERK<ref name=":3" />
|Overactive RAS 
|Constitutive activation of RAS and ERK 
|-
|PI3K/AKT<ref name=":3" />
|Dysregulation 
|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">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==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=":9" />
** 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=":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=":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==

*No known familiar forms as of yet.

==Additional Information==

*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==

*[[HAEM5:Hepatosplenic T-cell lymphoma|Hepatosplenic T-cell lymphoma]]

==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 [[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>.
==Other Sections==
Cancer Category


*[[HAEM4:Mature T- and NK-cell Neoplasms|Mature T- and NK-cell Neoplasm]]

[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases T]]