Compendium of Cancer Genome Aberrations

HAEM5:Aggressive NK-cell leukaemia: Difference between revisions

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{{DISPLAYTITLE:Aggressive NK-cell leukaemia}}
{{DISPLAYTITLE:Aggressive NK-cell leukaemia}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


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Case Western Reserve University, Cleveland, OH
Case Western Reserve University, Cleveland, OH
__TOC__
==WHO Classification of Disease==
==WHO Classification of Disease==


Aggressive NK-cell Leukaemia  
Aggressive NK-cell Leukaemia  


==Definition / Description of Disease==
==Related Terminology==
Aggressive NK-cell leukaemia is a malignant proliferation of NK-cells, often associated with EBV infection, however, a subset of cases could be EBV negative. The disease has an extremely aggressive clinical course with poor response to chemotherapy, frequent relapses noted in patient who have had previously achieved complete remission (+/- bone marrow transplantation).


==Synonyms / Terminology==
Aggressive NK-cell leukaemia/lymphoma
==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" />'''''
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":1" /><blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Clinical Features==
Most common presentation is with constitutional symptoms and frequently associated hepatosplenomegaly is noted on physical examination.<ref name=":1" /><ref name=":4" /> 
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|Constitutional symptoms (weight loss, fever, night sweats)
|Acceptable
 
|Aggressive NK-cell leukaemia/lymphoma
Hepatosplenomegaly common
 
Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome
|-
|-
|'''Laboratory Findings'''
|Not Recommended
|Markedly elevated serum lactate dehydrogenase (LDH) levels
|NK-large granular lymphocyte leukaemia; aggressive large granular lymphocyte leukaemia
 
Circulating FASL
 
Variable percentage of circulating leukemic cells
 
Anemia, neutropenia, thrombocytopenia
|}
|}


==Gene Rearrangements==


<blockquote class="blockedit">{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}</blockquote>
Due to the rarity of this lymphoma the data in recurrent chromosomal rearrangement is extremely scant. There have been chromosomal rearrangements reported in association with the aggressive NK-cell leukaemia, however, none of them are considered specific for the disease.
 
 
'''Signs and Symptoms:'''
 
*Constitutional symptoms, e.g, fever, general malaise
*Hepatosplenomegaly common
*Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome
 
'''Laboratory Findings:'''
 
*Markedly elevated serum lactate dehydrogenase (LDH) levels
*Circulating FASL
*Variable % of circulating leukaemic cells
*Anaemia, neutropenia, thrombocytopenia
 
 
<nowiki>*</nowiki>EBV-negative cases may occur ''de novo'' or transform from chronic lymphoproliferative disorder of NK cells
 
 
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":1" /><ref name=":4">{{Cite journal|last=Kim|first=Wook Youn|last2=Montes-Mojarro|first2=Ivonne A.|last3=Fend|first3=Falko|last4=Quintanilla-Martinez|first4=Leticia|date=2019|title=Epstein-Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases|url=https://pubmed.ncbi.nlm.nih.gov/30931288|journal=Frontiers in Pediatrics|volume=7|pages=71|doi=10.3389/fped.2019.00071|issn=2296-2360|pmc=6428722|pmid=30931288}}</ref><blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Sites of Involvement==
 
Peripheral blood, bone marrow, liver, spleen, and lymph nodes are frequently involved. Extranodal involvement sites are organs including skin, lungs, soft tissue and omentum has also been reported.<ref name=":5" />
 
 
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":5">{{Cite journal|last=Hue|first=Susan Swee-Shan|last2=Oon|first2=Ming Liang|last3=Wang|first3=Shi|last4=Tan|first4=Soo-Yong|last5=Ng|first5=Siok-Bian|date=2020-01|title=Epstein–Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach|url=https://linkinghub.elsevier.com/retrieve/pii/S0031302519304210|journal=Pathology|language=en|volume=52|issue=1|pages=111–127|doi=10.1016/j.pathol.2019.09.011}}</ref><blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Morphologic Features==
 
 
'''Peripheral Blood'''
 
*Variable; May appear as:
**Normal large granular lymphocytes or
**Intermediate to large cells with atypical nuclei (enlarged, irregular folding, open chromatin or distinct nucleoli) and moderate pale or lightly basophilic cytoplasm containing fine, coarse or no azurophilic granules.<ref name=":1" />
 
'''Bone Marrow:'''
 
*Interstitial or intrasinusoidal infiltrating pattern, which may be extensive, focal or subtle<ref name=":0" />
*May have interspersed reactive histiocytes with haemophagocytosis


'''Tissue:'''
*Diffuse or patchy destructive infiltrates
*Monotonous medium sized cells
*Round or highly irregular nuclei with condensed chromatin and small nucleoli
*Frequently admixed apoptotic bodies
*Necrosis common
*+/- angioinvasion
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":1">Chan, JKC et al., (2017). Aggressive NK-cell leukaemia, 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, p353-354.</ref><blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
==Immunophenotype==
The leukaemic cells show demonstrate the following phenotypic expression.<ref name=":1" /><ref name=":0" />
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!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
|-
|-
|Positive (universal)||CD2, CD3-epsilon, CD56, CD94, cytotoxic molecules (TIA1, Granzyme B, perforin A), FASL, c-MYC
|
|
|
|
|
|
|
|
|}
 
==Individual Region Genomic Gain/Loss/LOH==
{| class="wikitable sortable"
|-
|-
|Positive (subset)||CD16 (75%), CD11b, EBER, p53, pSTAT3, PD-L1, BCL2
!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
|-
|-
|Negative (universal)||surface CD3, CD4, CD5, CD57 (usually), CD158a/b/e, TCR alpha/beta, TCR gamma/delta
|<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).
|-
|-
|Negative (subset)||CD7, CD45
|<span class="blue-text">EXAMPLE:</span>
|}
8
 
|<span class="blue-text">EXAMPLE:</span> Gain
 
|<span class="blue-text">EXAMPLE:</span>
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":1" /><ref name=":0" /><blockquote class="blockedit">
chr8
<center><span style="color:Maroon">'''End of V4 Section'''</span>
|<span class="blue-text">EXAMPLE:</span>
----
Unknown
</blockquote>
|<span class="blue-text">EXAMPLE:</span> D, P
==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)*
|
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|-
|WHO Desirable Criteria (Genetics)*
|<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.
|-
|-
|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==
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
{| class="wikitable"
|+
|Acceptable
|
|
|-
|
|Not Recommended
|
|
|
|
|
|}
|}


==Gene Rearrangements==
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">{{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><ref name=":1">Chan, JKC et al., (2017). Aggressive NK-cell leukaemia, 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, p353-354.</ref><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>
 
Due to the rarity of this lymphoma the data in recurrent chromosomal rearrangement is extremely scant. There have been chromosomal rearrangements reported in association with the aggressive NK-cell leukaemia, however, none of them are considered specific for the disease.
==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" />


{| class="wikitable sortable"
{| class="wikitable sortable"
Line 231: Line 160:
|}
|}


<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
==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.


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosome!!Gain/Loss/Amp/LOH<br />
!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
|-
|-
|1q23.1-q23.2
|<span class="blue-text">EXAMPLE:</span>
|Gain
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
|
|
|-
|-
|1q31.3-q44
|<span class="blue-text">EXAMPLE:</span>
|Gain
Microsatellite instability - hypermutated
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|-
|-
|7p15.1-q22.3
|
|Loss
|
|-
|
|17p13.1
|
|Loss
|
|}
|
|}
 
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":0" /><ref name=":1" /><blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==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.


==Gene Mutations (SNV/INDEL)==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!Diagnostic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|}
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''


<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|<span class="blue-text">EXAMPLE:</span> T
|<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
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|<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
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|-
|
|
|
|
|
|
|
|}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.


 
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>''  
Due to rare nature of disease, cytogenetics data is limited. However, common abnormalities include del(6)(q21q25) and del(11q).
 
Complex karyotypes with unbalanced rearrangements are frequently seen.
 
 
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":2" /><blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
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</blockquote>
</blockquote>
==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" />''  


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>
Line 296: Line 249:
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene; Genetic Alteration!!Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)!!Prevalence (COSMIC /  TCGA / Other)!!Concomitant Mutations!!Mutually Exclusive Mutations
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
Line 345: Line 298:
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.


<br />


<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!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence <ref name=":2" />
|-
|JAK/STAT/c-MYC pathway (including ''STAT3, STAT5B, STAT5A, JAK2, JAK3, STAT6, SOCS31, SOCS3'' and ''PTPN11'')||Oncogene
|Gain of function||21 - 66.6%
|-
|RAS/MAPK pathway
|Oncogene
|Gain of function
|16.7 - 29%
|-
|''TP53''
|Tumor suppressor
|Loss of function
|7 -50%
|-
|''BCL2''
|Oncogene
|Gain of function
|N/A
|}
'''JAK/STAT/c-MYC'''
*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''
<blockquote class="blockedit">{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><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><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><ref name=":3" /><blockquote class="blockedit">
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<blockquote class="blockedit">
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</blockquote>
==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" />


 
<br />
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</blockquote>
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==


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==Genetic Diagnostic Testing Methods==


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Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.<ref name=":0" />
==Familial Forms==


N/A


*Upregulated JAK/STAT-MYC biosynthesis axis due to upstream STAT3 activation of the MYC transcription program. *
==Additional Information==
*Alterations in RAS-MAPK pathway also identified
This disease is <u>defined/characterized</u> as detailed below:
*Epigenetic modifier genes (e.g ''BCOR, KMT2D/MLL2'', ''SETD2'', ''PRDM9'', ''CREBBP'', and ''TET2'')
*DNA damage repair (''TP53, ASXL1, ASXL2, BRINP3)''
*mRNA splicing factors ''(PRPF40B)''


*Aggressive NK-cell leukaemia is a malignant proliferation of NK-cells, often associated with EBV infection, however, a subset of cases could be EBV negative. The disease has an extremely aggressive clinical course with poor response to chemotherapy, frequent relapses noted in patient who have had previously achieved complete remission (+/- bone marrow transplantation).


<nowiki>*</nowiki>Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.<ref name=":2" />
The <u>epidemiology/prevalence</u> of this disease is detailed below:


*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" /> 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">{{Cite journal|last=Kim|first=Wook Youn|last2=Montes-Mojarro|first2=Ivonne A.|last3=Fend|first3=Falko|last4=Quintanilla-Martinez|first4=Leticia|date=2019|title=Epstein-Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases|url=https://pubmed.ncbi.nlm.nih.gov/30931288|journal=Frontiers in Pediatrics|volume=7|pages=71|doi=10.3389/fped.2019.00071|issn=2296-2360|pmc=6428722|pmid=30931288}}</ref>'''''


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The <u>clinical features</u> of this disease are detailed below:
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*Most common presentation is with constitutional symptoms and frequently associated hepatosplenomegaly is noted on physical examination.<ref name=":1" /><ref name=":4" /> EBV-negative cases may occur ''de novo'' or transform from chronic lymphoproliferative disorder of NK cells.
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Signs and symptoms - Constitutional symptoms (weight loss, fever, night sweats); Hepatosplenomegaly common; Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome
----
 
</blockquote>
Laboratory findings - Markedly elevated serum lactate dehydrogenase (LDH) levels; Circulating FASL; Variable percentage of circulating leukemic cells; Anemia, neutropenia, thrombocytopenia
</blockquote>
 
==Genetic Diagnostic Testing Methods==
The <u>sites of involvement</u> of this disease are detailed below:
 
*Peripheral blood, bone marrow, liver, spleen, and lymph nodes are frequently involved. Extranodal involvement sites are organs including skin, lungs, soft tissue and omentum has also been reported.<ref name=":5">{{Cite journal|last=Hue|first=Susan Swee-Shan|last2=Oon|first2=Ming Liang|last3=Wang|first3=Shi|last4=Tan|first4=Soo-Yong|last5=Ng|first5=Siok-Bian|date=2020-01|title=Epstein–Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach|url=https://linkinghub.elsevier.com/retrieve/pii/S0031302519304210|journal=Pathology|language=en|volume=52|issue=1|pages=111–127|doi=10.1016/j.pathol.2019.09.011}}</ref>
 
The <u>morphologic features</u> of this disease are detailed below:
 
'''Peripheral Blood'''
 
*Variable; May appear as:
**Normal large granular lymphocytes or
**Intermediate to large cells with atypical nuclei (enlarged, irregular folding, open chromatin or distinct nucleoli) and moderate pale or lightly basophilic cytoplasm containing fine, coarse or no azurophilic granules.<ref name=":1" />
 
'''Bone Marrow:'''
 
*Interstitial or intrasinusoidal infiltrating pattern, which may be extensive, focal or subtle<ref name=":0" />
*May have interspersed reactive histiocytes with haemophagocytosis
 
'''Tissue:'''
 
*Diffuse or patchy destructive infiltrates
*Monotonous medium sized cells
*Round or highly irregular nuclei with condensed chromatin and small nucleoli
*Frequently admixed apoptotic bodies
*Necrosis common
*+/- angioinvasion
 
The <u>immunophenotype</u> of this disease is detailed below:


Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.<ref name=":0" />
*The leukaemic cells show demonstrate the following phenotypic expression.<ref name=":1" /><ref name=":0" />


Positive (universal) - CD2, CD3-epsilon, CD56, CD94, cytotoxic molecules (TIA1, Granzyme B, perforin A), FASL, c-MYC


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Positive (subset) - CD16 (75%), CD11b, EBER, p53, pSTAT3, PD-L1, BCL2
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</blockquote>
==Familial Forms==


N/A
Negative (universal) - surface CD3, CD4, CD5, CD57 (usually), CD158a/b/e, TCR alpha/beta, TCR gamma/delta


==Additional Information==
Negative (subset) - CD7, CD45
N/A


==Links==
==Links==
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[[HAEM5:Extranodal NK/T-cell lymphoma|Extranodal NK/T-cell lymphoma]]
[[HAEM5:Extranodal NK/T-cell lymphoma|Extranodal NK/T-cell lymphoma]]


[[Hepatosplenic T-cell Lymphoma (HSTCL)]]
[[HAEM5:Hepatosplenic T-cell lymphoma|Hepatosplenic T-cell Lymphoma]]


[[Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK)]]
[[HAEM5:NK-large granular lymphocytic leukaemia|NK-large Granular Lymphocytic Leukaemia]]


==References==
==References==
Retrieved from "https://test.ccga.io/index.php/HAEM5:Aggressive_NK-cell_leukaemia"