HAEM5:Aggressive NK-cell leukaemia: Difference between revisions
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==Epidemiology / Prevalence== | ==Epidemiology / Prevalence== | ||
Aggressive NK-cell leukaemia impacts young to middle-aged adults with peak incidence during 3rd and 5th decades of life (Mean age: 40 years).<ref name=":1" /> There is no gender predilection and most prevalent in Asia, Central and South America.<ref name=":0">{{Cite journal|last=El Hussein|first=Siba|last2=Patel|first2=Keyur P.|last3=Fang|first3=Hong|last4=Thakral|first4=Beenu|last5=Loghavi|first5=Sanam|last6=Kanagal-Shamanna|first6=Rashmi|last7=Konoplev|first7=Sergej|last8=Jabbour|first8=Elias J.|last9=Medeiros|first9=L. Jeffrey|date=09 2020|title=Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32590457|journal=The American Journal of Surgical Pathology|volume=44|issue=9|pages=1235–1243|doi=10.1097/PAS.0000000000001518|issn=1532-0979|pmid=32590457}}</ref> Median survival is very short, <2 months. EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations.<ref name=":2" /> EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells.'''''<ref name=":4" />''''' | Aggressive NK-cell leukaemia impacts young to middle-aged adults with peak incidence during 3rd and 5th decades of life (Mean age: 40 years).<ref name=":1" /> There is no gender predilection and most prevalent in Asia, Central and South America.<ref name=":0">{{Cite journal|last=El Hussein|first=Siba|last2=Patel|first2=Keyur P.|last3=Fang|first3=Hong|last4=Thakral|first4=Beenu|last5=Loghavi|first5=Sanam|last6=Kanagal-Shamanna|first6=Rashmi|last7=Konoplev|first7=Sergej|last8=Jabbour|first8=Elias J.|last9=Medeiros|first9=L. Jeffrey|date=09 2020|title=Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32590457|journal=The American Journal of Surgical Pathology|volume=44|issue=9|pages=1235–1243|doi=10.1097/PAS.0000000000001518|issn=1532-0979|pmid=32590457}}</ref> Median survival is very short, <2 months. EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations.<ref name=":2">{{Cite journal|last=El Hussein|first=Siba|last2=Medeiros|first2=L. Jeffrey|last3=Khoury|first3=Joseph D.|date=10 09, 2020|title=Aggressive NK Cell Leukemia: Current State of the Art|url=https://pubmed.ncbi.nlm.nih.gov/33050313|journal=Cancers|volume=12|issue=10|doi=10.3390/cancers12102900|issn=2072-6694|pmc=7600035|pmid=33050313}}</ref> EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells.'''''<ref name=":4" />''''' | ||
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==Individual Region Genomic Gain/Loss/LOH== | ==Individual Region Genomic Gain/Loss/LOH== | ||
There have been a few chromosomal abnormalities associated with aggressive NK-cell leukaemia as listed below, however, the specificity along with prognostic and therapeutic significance is unknown.<ref name=":2" /> | There have been a few chromosomal abnormalities associated with aggressive NK-cell leukaemia as listed below, however, the specificity along with prognostic and therapeutic significance is unknown.<ref name=":2" /><ref name=":1" /><ref name=":0" /> | ||
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==Characteristic Chromosomal or Other Global Mutational Patterns== | ==Characteristic Chromosomal or Other Global Mutational Patterns== | ||
Due to rare nature of disease, cytogenetics data is limited. The common abnormalities include del(6)(q21q25) and del(11q), however, none of these abnormalities are specific and their clinical significance is unknown.<ref name=":2" /> Complex karyotypes with unbalanced rearrangements are frequently seen. | Due to rare nature of disease, cytogenetics data is limited. The common abnormalities include del(6)(q21q25) and del(11q), however, none of these abnormalities are specific and their clinical significance is unknown.<ref name=":2" /> Complex karyotypes with unbalanced rearrangements are frequently seen. | ||
==Gene Mutations (SNV/INDEL)== | ==Gene Mutations (SNV/INDEL)== | ||
Mutations in the ''JAK-STAT'' pathway appear to be mutually exclusive.<ref name=":3" /> Most ''STAT3'' and ''STAT5B'' mutations localized to exons 20 and 21 encoding the Src homology 2 (SH2) domain, which causes ''STAT'' dimerization. Other mutations identified: 9p copy gains (containing ''JAK2),'' point mutation in protein tyrosine phosphatase (''PTPRK'') (tumor suppressor that negatively regulates ''STAT3''). mutations in ''PTPN4'' and ''PTPN23.<ref name=":2" /><ref name=":7" />'' | Mutations in the ''JAK-STAT'' pathway appear to be mutually exclusive.<ref name=":3">{{Cite journal|last=Huang|first=Liang|last2=Liu|first2=Dan|last3=Wang|first3=Na|last4=Ling|first4=Shaoping|last5=Tang|first5=Yuting|last6=Wu|first6=Jun|last7=Hao|first7=Lingtong|last8=Luo|first8=Hui|last9=Hu|first9=Xuelian|date=2018-02|title=Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia|url=http://www.nature.com/articles/cr2017146|journal=Cell Research|language=en|volume=28|issue=2|pages=172–186|doi=10.1038/cr.2017.146|issn=1001-0602|pmc=PMC5799812|pmid=29148541}}</ref> Most ''STAT3'' and ''STAT5B'' mutations localized to exons 20 and 21 encoding the Src homology 2 (SH2) domain, which causes ''STAT'' dimerization. Other mutations identified: 9p copy gains (containing ''JAK2),'' point mutation in protein tyrosine phosphatase (''PTPRK'') (tumor suppressor that negatively regulates ''STAT3''). mutations in ''PTPN4'' and ''PTPN23.<ref name=":2" /><ref name=":7">{{Cite journal|last=Gao|first=Juehua|last2=Zhang|first2=Yanming|last3=Yaseen|first3=Nabeel R.|last4=Fang|first4=Yuqiang|last5=Lu|first5=Xinyan|last6=Sukhanova|first6=Madina|last7=Chen|first7=Qing|last8=Chen|first8=Yi-Hua|date=2020-11|title=Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma|url=https://linkinghub.elsevier.com/retrieve/pii/S0046817720301702|journal=Human Pathology|language=en|volume=105|pages=20–30|doi=10.1016/j.humpath.2020.08.008}}</ref>'' | ||
Molecular abnormalities present possible therapeutic implications. Dufva et al identified high sensitivity of ANKL cell lines to JAK and BCL2 inhibition. Other possibly effective drug classes are heat shock protein 90 (HSP90) inhibitors, polo-like kinase (PLK) inhibitors, aurora kinase (AURK) inhibitors, cyclin-dependent kinase inhibitors, and histone deacetylase inhibitors.<ref name=":6">{{Cite journal|last=Dufva|first=Olli|last2=Kankainen|first2=Matti|last3=Kelkka|first3=Tiina|last4=Sekiguchi|first4=Nodoka|last5=Awad|first5=Shady Adnan|last6=Eldfors|first6=Samuli|last7=Yadav|first7=Bhagwan|last8=Kuusanmäki|first8=Heikki|last9=Malani|first9=Disha|date=04 19, 2018|title=Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target|url=https://pubmed.ncbi.nlm.nih.gov/29674644|journal=Nature Communications|volume=9|issue=1|pages=1567|doi=10.1038/s41467-018-03987-2|issn=2041-1723|pmc=5908809|pmid=29674644}}</ref> | Molecular abnormalities present possible therapeutic implications. Dufva et al identified high sensitivity of ANKL cell lines to JAK and BCL2 inhibition. Other possibly effective drug classes are heat shock protein 90 (HSP90) inhibitors, polo-like kinase (PLK) inhibitors, aurora kinase (AURK) inhibitors, cyclin-dependent kinase inhibitors, and histone deacetylase inhibitors.<ref name=":6">{{Cite journal|last=Dufva|first=Olli|last2=Kankainen|first2=Matti|last3=Kelkka|first3=Tiina|last4=Sekiguchi|first4=Nodoka|last5=Awad|first5=Shady Adnan|last6=Eldfors|first6=Samuli|last7=Yadav|first7=Bhagwan|last8=Kuusanmäki|first8=Heikki|last9=Malani|first9=Disha|date=04 19, 2018|title=Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target|url=https://pubmed.ncbi.nlm.nih.gov/29674644|journal=Nature Communications|volume=9|issue=1|pages=1567|doi=10.1038/s41467-018-03987-2|issn=2041-1723|pmc=5908809|pmid=29674644}}</ref> | ||
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Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) 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 cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content. | ||
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==Epigenomic Alterations== | ==Epigenomic Alterations== | ||
Mutations seen in epigenetic regulatory molecules including RNA helicase ''DDX3X'' (28%), ''TET2'' (28%), ''CREBBP'' (21%), and ''MLL2'' (21%) have been reported.<ref name=":2" /><ref name=":3" /> | Mutations seen in epigenetic regulatory molecules including RNA helicase ''DDX3X'' (28%), ''TET2'' (28%), ''CREBBP'' (21%), and ''MLL2'' (21%) have been reported.<ref name=":2" /><ref name=":3" /> | ||
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==Genes and Main Pathways Involved== | ==Genes and Main Pathways Involved== | ||