Compendium of Cancer Genome Aberrations

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

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


No known recurrent copy number gain/loss/LOH, chromosomal abnormalities have been reported in a few cases.<sup>[7]</sup> <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
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>
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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.
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>
 
<sup>[8]</sup> <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|''STAT3'' <sup>[1]</sup>  
|''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<sup>[1].</sup> Codons N647I<sup>[9]</sup>,K658S<sup>[9]</sup>, and K658F<sup>[22]</sup> are also affected  
|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 <sup>[31]</sup>  
|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 <sup>[11]</sup>  
|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  
|D, P, T  
|WHO, NCCN  
|WHO, NCCN  
|STAT3 mutation has been associated with statistically significant neutropenia, thrombocytopenia, and reduced numbers of most normal residual blood-leukocyte subsets<sup>[22]</sup>  
|STAT3 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>


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




Patients with STAT 3 mutation required treatment more frequently when compared to patients with STAT3 wild type<sup>[18]</sup>  
One prospective study showed a predictive response to methotrexate therapy in a small group of patients with STAT3 Y640F mutated genotype<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>




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


STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<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>


STAT3 mutation can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<sup>[12]</sup>  
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 <sup>[1]</sup> <br />
|STAT5B <ref name=":9" /><br />
|Gain of function src-like homologue 2 (SH2) domain of STAT5.  
|Gain of function src-like homologue 2 (SH2) domain of STAT5.  
Mutations include<sup>[19]</sup>:  
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
N642H
Q706L
S715F
T628S
P685R


V712E mutation of STAT5B is in the transactivation domain<sup>[19]</sup>
Y665F 


Mutations in the coiled-coil domain: CCD, Q220H <sup>[19]</sup>
Q706L 


Mutations in the DNA binding domain: DBD, E433G/K <sup>[19]</sup>
S715F 


Mutations in the inter-domain region: P702A <sup>[19]</sup>
T628S 
|Other <sup>[32]</sup>
|Common <sup>[20]</sup>
|D,P,T
|WHO, NCCN
|N642H mutation (associated with more aggressive disease)<sup>[13][14]</sup>


P685R


Clones can acquire multiple STAT5B mutations <sup>[19]</sup>  
V712E mutation of STAT5B is in the transactivation domain<ref name=":14" />  


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


STAT5B mutations can also be seen in other T-cell lymphomas including hepatosplenic T-cell lymphoma<sup>[12</sup>
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" />


N642H mutation is associated with CD3+/CD56+ phenotype<sup>[14]</sup>  
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 <sup>[19][20]</sup>
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 <sup>[1]</sup>  
|TNFAIP3 <ref name=":9" />
|Loss of function  
|Loss of function  
Somatic mutations:
Somatic mutations:
Line 227: Line 235:
A717T  
A717T  


F127C <sup>[9]</sup>
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 <sup>[33]</sup>  
|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 <sup>[46]</sup>  
|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  
|P,T  
|WHO  
|WHO  
|TNFAIP 3 mutation has been correlated with increased overall survival <sup>[17]</sup>  
|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>  
 
TNFAIP3 itself is a NF‐κB target gene<sup>[15]</sup>  
 


In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (''p''  = 0.004)<sup>[9]</sup>  
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 <sup>[1]</sup>  
|TET2 <ref name=":9" />
|Loss of function <sup>[26]</sup>  
|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 <sup>[34]</sup>  
|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 <sup>[46]</sup>  
|Common <ref name=":16" />
|N/A  
|N/A  
|WHO
|WHO
|Found to be the most prevalent mutation in myeloid neoplasm or myeloid clonal hematopoiesis coexisting with T-LGLL <sup>[30]</sup>  
|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 <sup>[1]</sup>  
|BCL11B <ref name=":9" />
|Missense H126R <sup>[43]</sup>  
|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 <sup>[35]</sup>  
|Other<ref>{{Cite journal|title=BCL11 transcription factor B|url=https://www.ncbi.nlm.nih.gov/datasets/gene/64919/|language=en}}</ref>
|Rare <sup>[43]</sup>  
|Rare<ref name=":17" />
|N/A  
|N/A  
|WHO  
|WHO  
|BCL11B is required for T-cell survival and overexpression could effectively increase T-cell activation and proliferation. <sup>[43]</sup>
|BCL11B is required for T-cell survival and overexpression could effectively increase T-cell activation and proliferation.<ref name=":17" />
|-
|-
|FLT3 <sup>[1]</sup>  
|FLT3<ref name=":9" />
|A high-impact Asp228Gly variant on JAK STAT has been demonstrated <sup>[44]</sup>  
|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 <sup>[36]</sup>  
|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 <sup>[44]</sup>  
|Rare<ref name=":18" />
|N/A  
|N/A  
|WHO  
|WHO  
|Connects STAT to the MAPK-Ras-ERK pathway and to IL-15 <sup>[44]</sup>  
|Connects STAT to the MAPK-Ras-ERK pathway and to IL-15<ref name=":18" />
|-
|-
|PTPN23 <sup>[1]</sup>  
|PTPN23<ref name=":9" />
|R641Q <sup>[45]</sup>
|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 <sup>[37]</sup>  
|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 <sup>[45]</sup>  
|Rare<ref name=":19" />
|N/A  
|N/A  
|WHO
|WHO
|Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation <sup>[45]</sup>  
|Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation<ref name=":19" />
|-
|-
|KMT2D <sup>[26]</sup>  
|KMT2D<ref name=":0" />
|Loss of function <sup>[26]</sup>  
|Loss of function<ref name=":0" />
|Other <sup>[38]</sup>  
|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 <sup>[46]</sup>  
|Recurrent<ref name=":16" />
|N/A  
|N/A  
|None
|None
|KMT2D has been linked to lymphomagenesis. <sup>[44]</sup>  
|KMT2D has been linked to lymphomagenesis.<ref name=":18" />  




KMT2D has been how to exhibit significant co-occurrence with STAT3 mutation <sup>[26]</sup>  
KMT2D has been how to exhibit significant co-occurrence with STAT3 mutation<ref name=":0" />
|-
|-
|CLIP3 <sup>[30]</sup>  
|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" />
|}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.
|-
|CLIP3<ref name=":1" />
|c.908A>T p.D303V


<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.


{| class="wikitable sortable"
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" />
|-
|-
!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>
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.


*Causing constitutive phosphorylation of the mutated proteins, and increased the transcriptional activity of STAT5B in vitro<ref name=":1" /><ref name=":2" />
<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote><br />
*
<blockquote class="blockedit"><center><span style="color:Maroon">'''End of V4 Section'''</span>
|GOF
|2%<ref name=":7">Rajala HL, Eldfors S, Kuusanmäki H, Van Adrichem AJ, Olson T, Lagström S, Andersson EI, Jerez A, Clemente MJ, Yan Y, Zhang D. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood, The Journal of the American Society of Hematology. 2013 May 30;121(22):4541-50.</ref>
|
*Take caution as STAT5B mutations can also be seen in other T-cell lymphomas including [[HAEM5:Hepatosplenic T-cell lymphoma|hepatosplenic T-cell lymphoma]]<ref name=":5" />
*N642H mutation is associated with CD3+/CD56+ phenotype<ref name=":8" />
|-
|TNFAIP3
|
*Somatic mutations<ref name=":6" />
**Y353X
**K354K
**Q741Q
**E630X
**A717T
**F127C
|LOF (Nonsense mutations)<ref name=":6" />
|Identified in 3/39 patients<ref name=":6" />
|
*In one study three of four of the patients with non‐synonymous TNFAIP3 alterations also harbored a STAT3 mutation (''p''  = 0.004)<ref name=":6" />
*TNFAIP3 itself is a NF‐κB target gene<ref>Zhang R, Shah MV, Yang J, Nyland SB, Liu X, Yun JK, Albert R, Loughran TP. Network model of survival signaling in large granular lymphocyte leukemia. Proceedings of the National Academy of Sciences. 2008 Oct 21;105(42):16308-13.</ref>
|}
<nowiki>*</nowiki>More comprehensive listing of specific mutations in these genes can be found elsewhere ([https://cancer.sanger.ac.uk/cosmic COSMIC], [https://www.cbioportal.org/ cBioPortal])
<br />
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
----
</blockquote>
</blockquote>
Line 354: Line 349:
**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 />
<br />
Line 359: Line 355:
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==


 
<span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: 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
|
|Apoptosis inhibition
|}
|}


<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>


*JAK/STAT<ref name=":9" />
**
**Constitutive activation
*NK-κB<ref name=":9" />
**Activation of this pathway
**Preventing apoptosis
*T-LGL's express high levels of FAS and FASL<ref name=":9">Lamy T, Moignet A, Loughran TP. LGL leukemia: from pathogenesis to treatment. Blood. 2017 Mar 2;129(9):1082-94.</ref>
**Resistant to FAS mediated apoptosis
**Leading to activation of prosurvival pathways
**Postulated to lead to neutropenia seen in these patients.
*RAS/RAF1/MEK1/ERK <ref name=":9" />
**Overactive RAS
**Constitutive activation of RAS and ERK
*PI3K/AKT<ref name=":9" />
**Dysregulation
**Contributing to apoptosis inhibition


<blockquote class="blockedit">
<blockquote class="blockedit">
Line 406: Line 391:
==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==
Line 419: Line 405:
==Additional Information==
==Additional Information==


*N/A
*PI3K-Akt has been found to be upregulated in KLRG1<sup>-</sup> CD8<sup>+</sup> T-LGLL. Studies are being conducted to examine treatment with linperlisib.<ref>{{Cite journal|last=Zhang|first=Lele|last2=Qiu|first2=Chen|last3=Li|first3=Ruonan|last4=Shen|first4=Yucan|last5=Tian|first5=Linzhu|last6=Chang|first6=Hong|last7=Liang|first7=Qian|last8=Pan|first8=Hong|last9=Gao|first9=Zhen|date=2025-04|title=KLRG1 re-defines a leukemic clone of CD8 effector T cells sensitive to PI3K inhibitor in T cell large granular lymphocytic leukemia|url=https://linkinghub.elsevier.com/retrieve/pii/S2666379125001090|journal=Cell Reports Medicine|language=en|volume=6|issue=4|pages=102036|doi=10.1016/j.xcrm.2025.102036|pmc=12047471|pmid=40147444}}</ref>
*Myleoid clonal hematopoiesis is associated with the presence of cytopenia in LGLL<ref name=":1" />


==Links==
==Links==
Retrieved from "https://test.ccga.io/index.php/HAEM5:T-large_granular_lymphocytic_leukaemia"