Compendium of Cancer Genome Aberrations

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

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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>


17% of patients with STAT3 mutations, had multiple mutations in the STAT3 gene, solely in cytotoxic CD8+ or NK cells.<ref name=":4" />
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 />
|STAT5B <ref name=":9" /><br />
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|-
|-
|TET2 <ref name=":9" />
|TET2 <ref name=":9" />
|Loss of function <ref>{{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>
|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>
|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" />
|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 <ref>{{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>
|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" />
|BCL11B <ref name=":9" />
Line 277: Line 277:
|Demonstrated in a patient with CD4+ T-LGLL without a STAT5B or STAT3 mutation<ref name=":19" />
|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" />
|-
|-
|TRAF3 <sup>[30]</sup>  
|TRAF3 <ref name=":1" />
|c.650A>T p.E217V <sup>[30]</sup>  
|c.650A>T p.E217V<ref name=":1" />
|Other <sup>[39]</sup>  
|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 <sup>[30]</sup>  
|Rare<ref name=":1" />
|N/A  
|N/A  
|None
|None
|Mutated putative driver <sup>[30]</sup>  
|Mutated putative driver<ref name=":1" />
|-
|-
|CLIP3 <sup>[30]</sup>  
|CLIP3<ref name=":1" />
|c.908A>T p.D303V  
|c.908A>T p.D303V  




c.917A>T p.K306M <sup>[30]</sup>  
 
|Other <sup>[40]</sup>  
c.917A>T p.K306M<ref name=":1" />
|Rare <sup>[30]</sup>  
|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  
|N/A  
|None
|None
|Mutated putative driver <sup>[30]</sup>  
|Mutated putative driver<ref name=":1" />
|-
|-
|FBXW2 <sup>[30]</sup>  
|FBXW2<ref name=":1" />
|c.683C>G p.A228G <sup>[30]</sup>  
|c.683C>G p.A228G <ref name=":1" />
|Other <sup>[41]</sup>  
|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 <sup>[30]</sup>  
|Rare<ref name=":1" />
|N/A  
|N/A  
|None
|None
|Mutated putative driver <sup>[30]</sup>  
|Mutated putative driver<ref name=":1" />
|-
|-
|CREBBP <sup>[30]</sup>  
|CREBBP<ref name=":1" />
|c.1178A>G p.N393S  
|c.1178A>G p.N393S  




c.4306T>C p.C1436R <sup>[30]</sup>  
c.4306T>C p.C1436R<ref name=":1" />
|Other
|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 <sup>[30]</sup>  
|Rare<ref name=":1" />
|N/A  
|N/A  
|None
|None
|A case is described of CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL<sup>[28]</sup>
|Mutated putative driver <ref name=":1" />
A case is described of CCL22 mutation co-occurring with both STAT3 and STAT5B in a CD4+TCR αβ T-LGLL <sup>[28]</sup>
|}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>
 
{| class="wikitable sortable"
|-
!Gene*!!Mutation!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence
!Additional information
|-
|-
|STAT3||
|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>
*Src-like homologue 2 (SH2) domain of STAT3
|SNV, somatic Mutation  
*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>
P46R<ref name=":2" />
|GOF||40-70%<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" />
*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
|-
|CCL22 co-occurring with a STAT3 mutation in a CD8+ TCR αβ T-LGLL<ref name=":2" />
|STAT5B
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.
*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" />
<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>
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</blockquote>
</blockquote>
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