Compendium of Cancer Genome Aberrations

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

[unchecked revision][checked revision]
← Older edit
VisualWikitext
Updated tables to fit new format
Tags: Visual edit Mobile edit Mobile web edit
 
(One intermediate revision by the same user not shown)
Line 1: Line 1:
{{DISPLAYTITLE:NK-large granular lymphocytic leukaemia}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
{{Under Construction}}
<blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Chronic Lymphoproliferative Disorder of NK Cells]].
}}</blockquote>
<br />
==Primary Author(s)*==
==Primary Author(s)*==


Line 38: Line 29:


{| class="wikitable"
{| class="wikitable"
|+
|Acceptable
|Acceptable
|Chronic lymphoproliferative disorder of NK cells; chronic NK-large granular lymphocyte lymphoproliferative disorder
|Chronic lymphoproliferative disorder of NK cells; chronic NK-large granular lymphocyte lymphoproliferative disorder
Line 56: Line 46:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|}
|}


Line 75: Line 65:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|}
|}


Line 96: Line 86:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|
|N/A
|}
|}


Line 114: Line 104:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|STAT3
|''STAT3''
|Exons 12-21 encoding the Src homology 2 (SH2 domain on two hotspots: D661 and Y640), driver mutation <ref name=":1">{{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://pubmed.ncbi.nlm.nih.gov/23596048|journal=Blood|volume=121|issue=22|pages=4541–4550|doi=10.1182/blood-2012-12-474577|issn=1528-0020|pmc=3668487|pmid=23596048}}</ref>
|Exons 12-21 encoding the Src homology 2 (SH2 domain on two hotspots: D661 and Y640), driver mutation <ref name=":1">{{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://pubmed.ncbi.nlm.nih.gov/23596048|journal=Blood|volume=121|issue=22|pages=4541–4550|doi=10.1182/blood-2012-12-474577|issn=1528-0020|pmc=3668487|pmid=23596048}}</ref>
|
|
Line 126: Line 116:
Commonly associated  with CD16high/CD57low or cytotoxic memory NK-LGL's <ref name=":3">{{Cite journal|last=Drillet|first=Gaëlle|last2=Pastoret|first2=Cédric|last3=Moignet|first3=Aline|last4=Lamy|first4=Thierry|last5=Marchand|first5=Tony|date=2022|title=Toward a Better Classification System for NK-LGL Disorders|url=https://pubmed.ncbi.nlm.nih.gov/35178350|journal=Frontiers in Oncology|volume=12|pages=821382|doi=10.3389/fonc.2022.821382|issn=2234-943X|pmc=8843930|pmid=35178350}}</ref>
Commonly associated  with CD16high/CD57low or cytotoxic memory NK-LGL's <ref name=":3">{{Cite journal|last=Drillet|first=Gaëlle|last2=Pastoret|first2=Cédric|last3=Moignet|first3=Aline|last4=Lamy|first4=Thierry|last5=Marchand|first5=Tony|date=2022|title=Toward a Better Classification System for NK-LGL Disorders|url=https://pubmed.ncbi.nlm.nih.gov/35178350|journal=Frontiers in Oncology|volume=12|pages=821382|doi=10.3389/fonc.2022.821382|issn=2234-943X|pmc=8843930|pmid=35178350}}</ref>
|-
|-
|TET2
|''TET2''
|Loss of function <ref name=":4">{{Cite journal|last=Pastoret|first=Cédric|last2=Desmots|first2=Fabienne|last3=Drillet|first3=Gaëlle|last4=Le Gallou|first4=Simon|last5=Boulland|first5=Marie-Laure|last6=Thannberger|first6=Alexia|last7=Doncker|first7=Anne-Violaine|last8=Salaun|first8=Véronique|last9=Damaj|first9=Gandhi Laurent|date=2021-06-10|title=Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells|url=https://pubmed.ncbi.nlm.nih.gov/33512451|journal=Blood|volume=137|issue=23|pages=3237–3250|doi=10.1182/blood.2020006721|issn=1528-0020|pmc=8351897|pmid=33512451}}</ref>
|Loss of function <ref name=":4">{{Cite journal|last=Pastoret|first=Cédric|last2=Desmots|first2=Fabienne|last3=Drillet|first3=Gaëlle|last4=Le Gallou|first4=Simon|last5=Boulland|first5=Marie-Laure|last6=Thannberger|first6=Alexia|last7=Doncker|first7=Anne-Violaine|last8=Salaun|first8=Véronique|last9=Damaj|first9=Gandhi Laurent|date=2021-06-10|title=Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells|url=https://pubmed.ncbi.nlm.nih.gov/33512451|journal=Blood|volume=137|issue=23|pages=3237–3250|doi=10.1182/blood.2020006721|issn=1528-0020|pmc=8351897|pmid=33512451}}</ref>
|Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation <ref name=":4" />
|Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation <ref name=":4" />
Line 138: Line 128:
Associated with thrombocytopenia <ref name=":4" />
Associated with thrombocytopenia <ref name=":4" />
|-
|-
|CCL22
|''CCL22''
|Gain of function <ref name=":6">{{Cite journal|last=Baer|first=Constance|last2=Kimura|first2=Shunsuke|last3=Rana|first3=Mitra S.|last4=Kleist|first4=Andrew B.|last5=Flerlage|first5=Tim|last6=Feith|first6=David J.|last7=Chockley|first7=Peter|last8=Walter|first8=Wencke|last9=Meggendorfer|first9=Manja|date=2022-05|title=CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk|url=https://pubmed.ncbi.nlm.nih.gov/35513723|journal=Nature Genetics|volume=54|issue=5|pages=637–648|doi=10.1038/s41588-022-01059-2|issn=1546-1718|pmc=9117519|pmid=35513723}}</ref>
|Gain of function <ref name=":6">{{Cite journal|last=Baer|first=Constance|last2=Kimura|first2=Shunsuke|last3=Rana|first3=Mitra S.|last4=Kleist|first4=Andrew B.|last5=Flerlage|first5=Tim|last6=Feith|first6=David J.|last7=Chockley|first7=Peter|last8=Walter|first8=Wencke|last9=Meggendorfer|first9=Manja|date=2022-05|title=CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk|url=https://pubmed.ncbi.nlm.nih.gov/35513723|journal=Nature Genetics|volume=54|issue=5|pages=637–648|doi=10.1038/s41588-022-01059-2|issn=1546-1718|pmc=9117519|pmid=35513723}}</ref>
|
|
Line 147: Line 137:
|Specific to NK-LGL <ref name=":3" />
|Specific to NK-LGL <ref name=":3" />
|-
|-
|TNFAIP3
|''TNFAIP3''
|Loss of function <ref name=":4" />
|Loss of function <ref name=":4" />
|TSG
|TSG
Line 156: Line 146:
|
|
|-
|-
|PI3K pathway genes
|''PI3K'' pathway genes
|PIK3CD activating mutation, PIK3AP1 mutation not previously described <ref name=":5" />
|PIK3CD activating mutation, PIK3AP1 mutation not previously described <ref name=":5" />
|
|
Line 165: Line 155:
|PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome <ref name=":5" />
|PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome <ref name=":5" />
|-
|-
|STAT5b
|''STAT5b''
|Exon 16 missense N642H mutation in the SH2 domain, driver mutation <ref name=":1" />
|Exon 16 missense N642H mutation in the SH2 domain, driver mutation <ref name=":1" />
|
|
Line 175: Line 165:


==Epigenomic Alterations==
==Epigenomic Alterations==
 
TET2 shows increased methylated regions in clonal NK-LGLs compared to normal NK-cells <ref name=":5" />
*TET2 shows increased methylated regions in clonal NK-LGLs compared to normal NK-cells <ref name=":5" />


==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
{| class="wikitable sortable"
!Gene; Genetic Alteration
!Pathway
!Pathophysiologic Outcome
|-
|''STAT3;'' gain of function mutations
|JAK/STAT signaling
|Persistent STAT3 activation leads to increased transcription of anti-apoptotic/pro-proliferative genes, clonal NK cell expansion, and enhanced survival; contributes to cytopenias and disease severity <ref>{{Cite journal|last=Marchand|first=Tony|last2=Lamy|first2=Thierry|last3=Loughran|first3=Thomas P.|date=2024-10-31|title=A modern view of LGL leukemia|url=https://pubmed.ncbi.nlm.nih.gov/38848524|journal=Blood|volume=144|issue=18|pages=1910–1923|doi=10.1182/blood.2023021790|issn=1528-0020|pmid=38848524}}</ref>
|-
|''TET2''; loss of function mutations
|DNA methylation/epigenetic regulation
|DNA methylation alters NK cell gene expression<ref>{{Cite journal|last=Semenzato|first=Gianpietro|last2=Teramo|first2=Antonella|last3=Barilà|first3=Gregorio|last4=Calabretto|first4=Giulia|last5=Rampazzo|first5=Elisa|last6=Buson|first6=Elena|last7=Zambello|first7=Renato|date=2025-06|title=NK-type large granular lymphocyte leukemia comes of age|url=https://pubmed.ncbi.nlm.nih.gov/40568352|journal=HemaSphere|volume=9|issue=6|pages=e70161|doi=10.1002/hem3.70161|issn=2572-9241|pmc=12194722|pmid=40568352}}</ref>
|-
|''CCL22''; gain of function mutations
|Chemokine signaling and microenvironmental interaction
|Alters NK cell interaction with the microenvironment, contributing to clonal dominance and unique immunophenotype <ref name=":6" />
|-
|''TNFAIP3''; inactivating alterations
|NF-κB negative regulation
|Loss of negative regulation enhances NF-κB signaling, promoting cell survival and anti-apoptotic transcription<ref name=":4" />
|-
|''KRAS, NOTCH1'' ''PTEN; PIK3R1'', ''PIK3CD,''  PIK3AP1
|RAS/MAPK and Pi3K/AKT pathways
|Dysregulation of the balance between survival and apoptosis <ref name=":8" /><ref name=":3" />
|}


Pathways involved include anti-apoptotic signaling and cell survival pathways. This includes the JAK/STAT pathway with constitutive activation of STAT3 and an activating mutation in STAT3. Also involved are RAS/MAPK and Pi3K/AKT pathways, which are constitutionally activated. <ref name=":3" />
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


*Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality <ref name=":7">{{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://pubmed.ncbi.nlm.nih.gov/28115367|journal=Blood|volume=129|issue=9|pages=1082–1094|doi=10.1182/blood-2016-08-692590|issn=1528-0020|pmid=28115367}}</ref>.
*Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality <ref name=":7">{{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://pubmed.ncbi.nlm.nih.gov/28115367|journal=Blood|volume=129|issue=9|pages=1082–1094|doi=10.1182/blood-2016-08-692590|issn=1528-0020|pmid=28115367}}</ref>.


*Mutational screen for STAT3, STAT5b, TET2, TNFAIP3 and CCL22 mutations may be more helpful when compared to KIR analysis on diagnostic work-up <ref name=":3" />.
*Mutational screen for ''STAT3, STAT5b, TET2, TNFAIP3'' and ''CCL22'' mutations may be more helpful when compared to KIR analysis on diagnostic work-up <ref name=":3" />.


*Absence of T-cell receptor gene rearrangement studies <ref name=":7" />.
*Absence of T-cell receptor gene rearrangements by PCR<ref name=":7" />.


*Sanger Sequencing.
*Sanger Sequencing.
Line 198: Line 211:


==Additional Information==
==Additional Information==
NK-LGLL is characterized by a persistent (>6 months) increase in peripheral NK cells (> 2 x 10^9/L) and a chronic indolent clinical course. Additional essential diagnostic criteria include flow cytometric evidence of peripheral blood or bone marrow involvement by a uniform population of sCD3(-), CD16(+) NK cells and demonstration of a restricted pattern of KIR expression.


This disease is <u>defined/characterized</u> as detailed below:
<u>Epidemiology/prevalence</u>: Median age: 60 years; does not show sex, racial, geographical, or genetic predisposition<ref name=":0">WHO Classification of Tumours Editorial Board, eds, WHO Classification of Tumours, Haematolymphoid Tumours Part A. 5th edition, IARC Press:Lyon, 2024.</ref>
 
*A neoplasm characterized by a persistent (>6 months) increase in peripheral NK cells (> 2 x 10^9/L) and a chronic indolent clinical course. Additional essential diagnostic criteria include flow cytometric evidence of peripheral blood or bone marrow involvement by a uniform population of sCD3(-), CD16(+) NK cells and demonstration of a restricted pattern of KIR expression.
*The differential diagnosis includes other mature T-cell neoplasms with a leukemic presentation. T-cell large granular lymphocytic leukemia is a disorder with clinical and pathological overlap; NK-LGL cannot be distinguished from T-LGL by cytological features. If there is prominent lymphocytosis, an aggressive NK-cell leukemia can be considered and NK-LGL is distinguished by an indolent clinical presentation and lack of nuclear EBV positivity.<ref name=":0">WHO Classification of Tumours Editorial Board, eds, WHO Classification of Tumours, Haematolymphoid Tumours Part A. 5th edition, IARC Press:Lyon, 2024.</ref>


The <u>epidemiology/prevalence</u> of this disease is detailed below:
<u>Clinical features</u>:
 
*Median age: 60 years
 
*Does not show sex, racial, geographical, or genetic predisposition<ref name=":0" />
 
The <u>clinical features</u> of this disease are detailed below:


*Signs and symptoms - Asymptomatic (incidental finding on complete blood counts); May occur in association with autoimmune disorders, solid tumors, hematological neoplasms, and neuropathy; Uncommon/atypical: splenomegaly, hepatomegaly, lymphadenopathy, skin involvement<ref name=":0" />
*Signs and symptoms - Asymptomatic (incidental finding on complete blood counts); May occur in association with autoimmune disorders, solid tumors, hematological neoplasms, and neuropathy; Uncommon/atypical: splenomegaly, hepatomegaly, lymphadenopathy, skin involvement<ref name=":0" />
*Laboratory findings - Lymphocytosis, variable neutropenia and/or anemia<ref name=":0" />
*Laboratory findings - Lymphocytosis, variable neutropenia and/or anemia<ref name=":0" />


The <u>sites of involvement</u> of this disease are detailed below:
<u>Sites of involvement:</u> Peripheral blood and bone marrow; uncommonly spleen<ref name=":0" />
 
*Peripheral blood and bone marrow
 
*Uncommon: spleen<ref name=":0" />
 
The <u>morphologic features</u> of this disease are detailed below:


*NK-cells are typically intermediate to large in size with small, round nuclei and moderate cytoplasm with fine or coarse azurophilic granules.
<u>Morphologic features</u>: NK-cells are typically intermediate to large in size with small, round nuclei and moderate cytoplasm with fine or coarse azurophilic granules. Intrasinusoidal and sometimes interstitial infiltration of bone marrow and possibly spleen.<ref name=":0" />


*Intrasinusoidal and sometimes interstitial infiltration of bone marrow and possibly spleen.<ref name=":0" />
<u>Immunophenotype</u>:


The <u>immunophenotype</u> of this disease is detailed below:
* Positive - CD16, CD56 (frequent), cytoplasmic CD3-epsilon, cytotoxic markers (TIA1, granzyme B & granzyme M), CD94


Positive - CD16, cytoplasmic CD3-epsilon, Cytotoxic markers (TIA1, granzyme B & granzyme M), CD94
* Decreased to negative - CD2, CD7, CD57, CD161; restricted or lack of expression - KIR isoforms (CD158a, b, c)


Positive (frequent) - CD56
* Negative - surface CD3, EBV
 
Decreased to negative - CD2, CD7, CD57, CD161
 
Restricted or lack of expression - KIR isoforms (CD158a, b, c)
 
Negative - surface CD3, EBV  


==Links==
==Links==


N/A<br />
N/A


==References==
==References==
<references />
<references />


<br />
==Notes==
<nowiki>*</nowiki>''Citation of this Page'': St. Louis H, Don M. “NK-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:NK-large_granular_lymphocytic_leukaemia</nowiki>.
 


==Notes==
<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.
<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):   
Prior Author(s):   
       
<nowiki>*</nowiki>''Citation of this Page'': “NK-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:NK-large_granular_lymphocytic_leukaemia</nowiki>.
[[Category:HAEM5]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:DISEASE]]
[[Category:Diseases N]]
[[Category:Diseases N]]
Retrieved from "https://test.ccga.io/index.php/HAEM5:NK-large_granular_lymphocytic_leukaemia"