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

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{{DISPLAYTITLE:T-large granular lymphocytic leukaemia}}
{{DISPLAYTITLE:T-large granular lymphocytic leukaemia}}[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[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)*==
==Primary Author(s)*==
Nicolas LaScala, DO


*Michelle Don, MD, MS
Michelle Don, MD, MS


==WHO Classification of Disease==
==WHO Classification of Disease==
Line 35: Line 27:
|}
|}


==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable"
|+
|WHO Essential Criteria (Genetics)*
|
|-
|WHO Desirable Criteria (Genetics)*
|
|-
|Other Classification
|
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
==Related Terminology==
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
 
{| class="wikitable"
{| class="wikitable"
|+
|Acceptable
|Acceptable
|
|T-cell lymphoproliferative disease of granular lymphocytes; T-cell large granular lymphocytic leukaemia
|-
|-
|Not Recommended
|Not Recommended
|
|T-cell large granular lymphocytosis; T-gamma lymphoproliferative disease
|}
|}


==Gene Rearrangements==
==Gene Rearrangements==


 
No know chromosomal rearrangements.  
Put your text here and fill in the table <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"
{| class="wikitable sortable"
|-
|-
Line 72: Line 48:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|N/A||N/A||N/A||N/A
|<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)
|N/A
|<span class="blue-text">EXAMPLE:</span>
|N/A
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).
|}
==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>  
{| class="wikitable sortable"
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
!Established Clinical Significance Per Guidelines - Yes or No (Source)
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
!Clinical Relevance Details/Other Notes
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|<span class="blue-text">EXAMPLE:</span> D
|
|<span class="blue-text">EXAMPLE:</span>
 
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|N/A
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
|N/A
|N/A
|N/A
|N/A
|N/A
|N/A
|}
==Characteristic Chromosomal or Other Global Mutational Patterns==


No characteristic chromosomal patterns have been identified.


Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
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 class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
{| class="wikitable sortable"
|<span class="blue-text">EXAMPLE:</span> N/A
|-
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
!Chromosomal Pattern
|<span class="blue-text">EXAMPLE:</span> T
!Molecular Pathogenesis
|
!Prevalence -
|<span class="blue-text">EXAMPLE:</span>
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
|}
==Gene Mutations (SNV/INDEL)==


Both balanced and unbalanced forms are observed by FISH (add references).
Somatic activating ''STAT3'' and ''STAT5b'' mutations are the most common SNVs in T-LGL.
{| class="wikitable sortable"
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
|<span class="blue-text">EXAMPLE:</span> N/A
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
|<span class="blue-text">EXAMPLE:</span> N/A
!Established Clinical Significance Per Guidelines - Yes or No (Source)
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
!Clinical Relevance Details/Other Notes
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|-
|
|''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>


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


*No known chromosomal rearrangements
N642H 


<blockquote class="blockedit">
Y665F 
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>


Q706L 


<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
S715F 
* 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
T628S  
*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">
P685R
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Individual Region Genomic Gain/Loss/LOH==


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


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>
Mutations in the coiled-coil domain: CCD, Q220H <ref name=":14" />  
{| 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'''
|-
|<span class="blue-text">EXAMPLE:</span>
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
chr7
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<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).
|-
|<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
|
|<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.
|-
|
|
|
|
|
|
|
|}


<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 or Other Global Mutational Patterns==


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


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>
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>
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
|TNFAIP3 <ref name=":9" />
!Molecular Pathogenesis
|Loss of function
!'''Prevalence -'''
Somatic mutations:
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
 
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
Y353X
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
 
!'''Clinical Relevance Details/Other Notes'''
K354K
|-
|<span class="blue-text">EXAMPLE:</span>
Co-deletion of 1p and 18q
|<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).
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|-
|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|-
|
|
|
|
|
|
|}


<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)==


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>


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>
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" />
{| class="wikitable sortable"
|-
|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" />
|-
|-
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
|FLT3<ref name=":9" />
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
|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>
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
|Other<ref>{{Cite journal|title=fms related receptor tyrosine kinase 3|url=https://www.ncbi.nlm.nih.gov/datasets/gene/2322/|language=en}}</ref>
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
|Rare<ref name=":18" />
!'''Clinical Relevance Details/Other Notes'''
|N/A
|WHO
|Connects STAT to the MAPK-Ras-ERK pathway and to IL-15<ref name=":18" />
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|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>
<br />
|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>
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|Rare<ref name=":19" />
|<span class="blue-text">EXAMPLE:</span> Oncogene
|N/A
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|WHO
|<span class="blue-text">EXAMPLE:</span> T
|Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation<ref name=":19" />
|<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).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|KMT2D<ref name=":0" />
<br />
|Loss of function<ref name=":0" />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|Other<ref>{{Cite journal|title=KMT2D lysine methyltransferase 2D [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/8085}}</ref>
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|Recurrent<ref name=":16" />
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|N/A
|<span class="blue-text">EXAMPLE:</span> P
|None
|
|Frequent co-occurrence of ''KMT2D'' and ''STAT3'' mutations<ref name=":0" />
|<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
|TRAF3 <ref name=":1" />
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|c.650A>T p.E217V<ref name=":1" />
|<span class="blue-text">EXAMPLE:</span> Oncogene
|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>
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|Rare<ref name=":1" />
|<span class="blue-text">EXAMPLE:</span> T
|N/A
|
|None
|
|Mutated putative driver<ref name=":1" />
|-
|-
|
|CLIP3<ref name=":1" />
|
|c.908A>T p.D303V
|
|
|
|
|
|}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>


Somatic activating STAT3 and STAT5b mutations are the most common SNVs in T-LGL.
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>
{| class="wikitable sortable"
|Rare<ref name=":1" />
|N/A
|None
|Mutated putative driver<ref name=":1" />
|-
|-
!Gene*!!Mutation!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence
|FBXW2<ref name=":1" />
!Additional information
|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" />
|-
|-
|STAT3||
|CREBBP<ref name=":1" />
*Src-like homologue 2 (SH2) domain of STAT3
|c.1178A>G p.N393S
*Most frequently affecting codons Y640 or D661<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>
**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>
c.4306T>C p.C1436R<ref name=":1" />
|'''GOF'''||40-70%<ref name=":2" />
|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" />
*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
|Mutated putative driver <ref name=":1" />
|-
|-
|STAT5B
|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  
*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" />
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>
|'''GOF'''
|Rare<ref name=":2" />
|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>
|N/A
|
|None
*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" />
|CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL<ref name=":2" />
*N642H mutation is associated with CD3+/CD56+ phenotype<ref name=":8" />
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.
|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==
==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 />
 
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!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
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|FAS and FASL<ref name=":3" />
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|Resistance to FAS mediated apoptosis
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|Activation of pro-survival pathways which is postulated to lead to neutropenia
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|RAS/RAF1/MEK1/ERK<ref name=":3" />
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|Overactive RAS
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|Constitutive activation of RAS and ERK
|-
|-
|
|PI3K/AKT<ref name=":3" />
|
|Dysregulation
|
|
|}
|}
<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">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


*Morphologic assessment, flow cytometry and immunohistochemistry
*Morphologic assessment, flow cytometry and immunohistochemistry  
*PCR to assess for clonality, T-cell receptor (TCR) gene rearrangements
*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==
==Familial Forms==
 
No known familiar forms as of yet.
*No known familiar forms as of yet.


==Additional Information==
==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>


*N/A
Myleoid clonal hematopoiesis is associated with the presence of cytopenia in LGLL<ref name=":1" />


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


==References==
==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 />
<references />
 
<br />


==Notes==
==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.
<nowiki>*</nowiki>''Citation of this Page'': LaScala N, Don M“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>.


Prior Author(s): 


       
<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.


<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>.
Prior Author(s): N/A 
==Other Sections==
==Other Sections==
Cancer Category
Cancer Category

Latest revision as of 22:41, 17 February 2026

Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Nicolas LaScala, DO

Michelle Don, MD, MS

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.

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

Individual Region Genomic Gain/Loss/LOH

No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in a few cases.[1]

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

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]

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

Gene Mutations (SNV/INDEL)

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

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 Frequent co-occurrence of KMT2D and STAT3 mutations[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.

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

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

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

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Lamy, Thierry; Moignet, Aline; Loughran, Thomas P. (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; Ramchandren, Radhakrishnan; Papenhausen, Peter; Loughran, Thomas P.; Sokol, Lubomir (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. {{cite journal}}: Check date values in: |date= (help)
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 "BlueBooksOnline". {{cite journal}}: Cite journal requires |journal= (help)
  4. ↑ 4.0 4.1 4.2 Johansson, Patricia; Bergmann, Anke; Rahmann, Sven; Wohlers, Inken; Scholtysik, René; Przekopowitz, Martina; Seifert, Marc; Tschurtschenthaler, Gertraud; Webersinke, Gerald (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. ↑ 5.0 5.1 Muñoz-García, Noemí; Jara-Acevedo, María; Caldas, Carolina; Bárcena, Paloma; López, Antonio; Puig, Noemí; Alcoceba, Miguel; Fernández, Paula; Villamor, Neus (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. PMID 33255665.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ↑ "STAT3 signal transducer and activator of transcription 3 [Homo sapiens (human)] - Gene - NCBI". {{cite journal}}: Cite journal requires |journal= (help)
  7. ↑ Koskela, Hanna L.M.; Eldfors, Samuli; Ellonen, Pekka; van Adrichem, Arjan J.; Kuusanmäki, Heikki; Andersson, Emma I.; Lagström, Sonja; Clemente, Michael J.; Olson, Thomas (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; Teramo, Antonella; Calabretto, Giulia; Vicenzetto, Cristina; Gasparini, Vanessa Rebecca; Pavan, Laura; Leoncin, Matteo; Vedovato, Susanna; Frigo, Anna Chiara (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. {{cite journal}}: Check date values in: |date= (help)
  9. ↑ Fei, Fei; Stehr, Henning; Zehnder, James L. (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; Zickl, L; Olson, T L; Wang, V; Zhang, D; Rajala, H L M; Hasanali, Z; Bennett, J M; Lazarus, H M (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. {{cite journal}}: Check date values in: |date= (help)
  11. ↑ 11.0 11.1 Yabe, Mariko; Medeiros, L. Jeffrey; Wang, Sa A.; Tang, Guilin; Bueso-Ramos, Carlos E.; Jorgensen, Jeffrey L.; Bhagat, Govind; Chen, Weina; Li, Shaoying (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. {{cite journal}}: Check date values in: |date= (help)
  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.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Bhattacharya, Dipabarna; Teramo, Antonella; Gasparini, Vanessa Rebecca; Huuhtanen, Jani; Kim, Daehong; Theodoropoulos, Jason; Schiavoni, Gianluca; Barilà, Gregorio; Vicenzetto, Cristina (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. PMID 35210405.
  14. ↑ "STAT5B signal transducer and activator of transcription 5B [Homo sapiens (human)] - Gene - NCBI". {{cite journal}}: Cite journal requires |journal= (help)
  15. ↑ Rajala, Hanna L. M.; Eldfors, Samuli; Kuusanmäki, Heikki; van Adrichem, Arjan J.; Olson, Thomas; Lagström, Sonja; Andersson, Emma I.; Jerez, Andres; Clemente, Michael J. (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. ↑ 16.0 16.1 Rajala, Hanna L. M.; Porkka, Kimmo; Maciejewski, Jaroslaw P.; Loughran, Thomas P.; Mustjoki, Satu (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.; Tanahashi, Takahiro; Sekiguchi, Nodoka; Gasparini, Vanessa Rebecca; Bortoluzzi, Sabrina; Kawakami, Toru; Matsuda, Kazuyuki; Mitsui, Takeki; Eldfors, Samuli (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; Bergmann, Anke; Rahmann, Sven; Wohlers, Inken; Scholtysik, René; Przekopowitz, Martina; Seifert, Marc; Tschurtschenthaler, Gertraud; Webersinke, Gerald (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". {{cite journal}}: Cite journal requires |journal= (help)
  20. ↑ 20.0 20.1 20.2 Upadhyayula, Bhanu Surabi; Saglimbeni, Grace S.; Gobel, Edie; Gobel, Abbi; Morris, Tyson J.; Surendra, Akaash; Hsia, Beau; Sood, Akshat; Tauseef, Abubakar (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. PMID 41482347. {{cite journal}}: Check date values in: |date= (help)
  21. ↑ Chen, Cunte; Chen, Zheng; Huang, Ling; Zhou, Lingling; Zhu, Lihua; Liu, Sichu; Luo, Gengxin; Li, Wenyu; Zeng, Chengwu (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. PMID 34526012.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ↑ Zhang, Ranran; Shah, Mithun Vinod; Yang, Jun; Nyland, Susan B.; Liu, Xin; Yun, Jong K.; Albert, Réka; Loughran, Thomas P. (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. ↑ 23.0 23.1 23.2 23.3 23.4 Cheon, HeeJin; Xing, Jeffrey C.; Moosic, Katharine B.; Ung, Johnson; Chan, Vivian W.; Chung, David S.; Toro, Mariella F.; Elghawy, Omar; Wang, John S. (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. PMID 35015834.
  24. ↑ "TET2 tet methylcytosine dioxygenase 2 [Homo sapiens (human)] - Gene - NCBI". {{cite journal}}: Cite journal requires |journal= (help)
  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; Gurnari, Carmelo; Bravo-Perez, Carlos; Kubota, Yasuo; Pagliuca, Simona; Guarnera, Luca; Williams, Nakisha D.; Durmaz, Arda; Ahmed, Arooj (2025-02). "Clonal hematopoiesis in large granular lymphocytic leukemia". Leukemia. 39 (2): 451–459. doi:10.1038/s41375-024-02460-y. ISSN 1476-5551. {{cite journal}}: Check date values in: |date= (help)
  26. ↑ 26.0 26.1 26.2 Andersson, E. I.; Rajala, H. L. M.; Eldfors, S.; Ellonen, P.; Olson, T.; Jerez, A.; Clemente, M. J.; Kallioniemi, O.; Porkka, K. (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. {{cite journal}}: Check date values in: |date= (help)
  27. ↑ "BCL11 transcription factor B". {{cite journal}}: Cite journal requires |journal= (help)
  28. ↑ 28.0 28.1 28.2 Coppe, A; Andersson, E I; Binatti, A; Gasparini, V R; Bortoluzzi, S; Clemente, M; Herling, M; Maciejewski, J; Mustjoki, S (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. {{cite journal}}: Check date values in: |date= (help)
  29. ↑ "fms related receptor tyrosine kinase 3". {{cite journal}}: Cite journal requires |journal= (help)
  30. ↑ 30.0 30.1 30.2 Andersson, Emma I.; Tanahashi, Takahiro; Sekiguchi, Nodoka; Gasparini, Vanessa Rebecca; Bortoluzzi, Sabrina; Kawakami, Toru; Matsuda, Kazuyuki; Mitsui, Takeki; Eldfors, Samuli (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". {{cite journal}}: Cite journal requires |journal= (help)
  32. ↑ "KMT2D lysine methyltransferase 2D [Homo sapiens (human)] - Gene - NCBI". {{cite journal}}: Cite journal requires |journal= (help)
  33. ↑ "TRAF3 TNF receptor associated factor 3 [Homo sapiens (human)] - Gene - NCBI". {{cite journal}}: Cite journal requires |journal= (help)
  34. ↑ "TRAF3 TNF receptor associated factor 3 [Homo sapiens (human)] - Gene - NCBI". {{cite journal}}: Cite journal requires |journal= (help)
  35. ↑ "F-box and WD repeat domain containing 2". {{cite journal}}: Cite journal requires |journal= (help)
  36. ↑ "CREBBP CREB binding lysine acetyltransferase [Homo sapiens (human)] - Gene - NCBI". {{cite journal}}: Cite journal requires |journal= (help)
  37. ↑ 37.0 37.1 37.2 37.3 37.4 Mizuno, Yuga; Kawakami, Toru; Higano, Daigo; Miyairi, Shotaro; Asakura, Ami; Kawakami, Fumihiro; Sato, Keijiro; Matsuzawa, Shuji; Nishina, Sayaka (2024-05-30). "CCL22 mutations in large granular lymphocytic leukemia". Haematologica. doi:10.3324/haematol.2024.285404. ISSN 1592-8721. PMC 11367240. PMID 38813714.
  38. ↑ "C-C motif chemokine ligand 2". {{cite journal}}: Cite journal requires |journal= (help)
  39. ↑ 39.0 39.1 39.2 Teramo, Antonella; Gattazzo, Cristina; Passeri, Francesca; Lico, Albana; Tasca, Giulia; Cabrelle, Anna; Martini, Veronica; Frezzato, Federica; Trimarco, Valentina (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; Mohebnasab, Maedeh; Angel, Marcela Riveros; Xie, Wei; Raess, Philipp W.; Cui, Wei; Press, Richard D.; Yang, Guang; Li, Peng (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; Qiu, Chen; Li, Ruonan; Shen, Yucan; Tian, Linzhu; Chang, Hong; Liang, Qian; Pan, Hong; Gao, Zhen (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. PMID 40147444. {{cite journal}}: Check date values in: |date= (help)CS1 maint: article number as page number (link)

Notes

*Citation of this Page: LaScala N, Don M“T-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/17/2026, https://ccga.io/index.php/HAEM5:T-large_granular_lymphocytic_leukaemia.


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