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.)]] | |||
==Primary Author(s)*== | ==Primary Author(s)*== | ||
Nicolas LaScala, DO | |||
Michelle Don, MD, MS | |||
==WHO Classification of Disease== | ==WHO Classification of Disease== | ||
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{| class="wikitable" | {| class="wikitable" | ||
|Acceptable | |Acceptable | ||
|T-cell lymphoproliferative disease of granular lymphocytes; T-cell large granular lymphocytic leukaemia | |T-cell lymphoproliferative disease of granular lymphocytes; T-cell large granular lymphocytic leukaemia | ||
| Line 49: | Line 39: | ||
==Gene Rearrangements== | ==Gene Rearrangements== | ||
No know chromosomal rearrangements. | No know chromosomal rearrangements. | ||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
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|N/A | |N/A | ||
|} | |} | ||
==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.<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 | 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" | {| class="wikitable sortable" | ||
|- | |- | ||
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|N/A | |N/A | ||
|} | |} | ||
==Characteristic Chromosomal or Other Global Mutational Patterns== | ==Characteristic Chromosomal or Other Global Mutational Patterns== | ||
No characteristic chromosomal patterns have been identified. | |||
One reported case with unique cytogenetic findings of a γδ variant T-cell LGL include: interstitial deletion of 3p21.31, monosomy X, trisomy 5, monosomy 21, and CN-LOH, located at 17q.<ref>{{Cite journal|last=Zhang|first=Ling|last2=Ramchandren|first2=Radhakrishnan|last3=Papenhausen|first3=Peter|last4=Loughran|first4=Thomas P.|last5=Sokol|first5=Lubomir|date=2014-09|title=Transformed aggressive γδ‐variant T‐cell large granular lymphocytic leukemia with acquired copy neutral loss of heterozygosity at 17q11.2q25.3 and additional aberrations|url=https://onlinelibrary.wiley.com/doi/10.1111/ejh.12313|journal=European Journal of Haematology|language=en|volume=93|issue=3|pages=260–264|doi=10.1111/ejh.12313|issn=0902-4441}}</ref> | |||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
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|N/A | |N/A | ||
|} | |} | ||
==Gene Mutations (SNV/INDEL)== | ==Gene Mutations (SNV/INDEL)== | ||
Somatic activating STAT3 and STAT5b mutations are the most common SNVs in T-LGL. | Somatic activating ''STAT3'' and ''STAT5b'' mutations are the most common SNVs in T-LGL. | ||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
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|WHO, NCCN | |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 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> | 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> | 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> | 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> | 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> | ||
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|N/A | |N/A | ||
|None | |None | ||
| | |Frequent co-occurrence of ''KMT2D'' and ''STAT3'' mutations<ref name=":0" /> | ||
|- | |- | ||
|TRAF3 <ref name=":1" /> | |TRAF3 <ref name=":1" /> | ||
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|CLIP3<ref name=":1" /> | |CLIP3<ref name=":1" /> | ||
|c.908A>T p.D303V | |c.908A>T p.D303V | ||
c.917A>T p.K306M<ref name=":1" /> | c.917A>T p.K306M<ref name=":1" /> | ||
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|CREBBP<ref name=":1" /> | |CREBBP<ref name=":1" /> | ||
|c.1178A>G p.N393S | |c.1178A>G p.N393S | ||
c.4306T>C p.C1436R<ref name=":1" /> | c.4306T>C p.C1436R<ref name=":1" /> | ||
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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. | |}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. | ||
==Epigenomic Alterations== | ==Epigenomic Alterations== | ||
Epigenetic inactivation of JAK/STAT pathway inhibitors | |||
*SOCS3 has a crucial role in regulating STAT3 activation<ref name=":10">{{Cite journal|last=Teramo|first=Antonella|last2=Gattazzo|first2=Cristina|last3=Passeri|first3=Francesca|last4=Lico|first4=Albana|last5=Tasca|first5=Giulia|last6=Cabrelle|first6=Anna|last7=Martini|first7=Veronica|last8=Frezzato|first8=Federica|last9=Trimarco|first9=Valentina|date=2013-05-09|title=Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23515927|journal=Blood|volume=121|issue=19|pages=3843–3854, S1|doi=10.1182/blood-2012-07-441378|issn=1528-0020|pmid=23515927}}</ref> | |||
*An epigenetic inhibition mechanism to SOCS3 gene is hypothesized<ref name=":10" /> | |||
*KIR3DL1 has been shown to be down-modulated by hypermethylation of the promoter<ref name=":10" /> | |||
*Mutations in KMT2D and TET2 have been found to significantly co-occur with STAT3 mutations<ref name=":0" /> | |||
==Genes and Main Pathways Involved== | ==Genes and Main Pathways Involved== | ||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
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|PI3K/AKT<ref name=":3" /> | |PI3K/AKT<ref name=":3" /> | ||
|Dysregulation | |Dysregulation | ||
| | | | ||
|} | |} | ||
==Genetic Diagnostic Testing Methods== | ==Genetic Diagnostic Testing Methods== | ||
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==Familial Forms== | ==Familial Forms== | ||
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> | |||
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]] | |||
==References== | ==References== | ||
<references /> | |||
==Notes== | ==Notes== | ||
<nowiki>*</nowiki> | <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>. | ||
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author. | |||
Prior Author(s): N/A | |||
==Other Sections== | ==Other Sections== | ||
Cancer Category | Cancer Category | ||