Compendium of Cancer Genome Aberrations

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

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{{DISPLAYTITLE:NK-large granular lymphocytic leukaemia}}
{{DISPLAYTITLE:NK-large granular lymphocytic leukaemia}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]


{{Under Construction}}
{{Under Construction}}


<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|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 class="blockedit">{{Box-round|title=HAEM5 Conversion Notes|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>
}}</blockquote>


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==Primary Author(s)*==
==Primary Author(s)*==


Michelle Don, MD
Hailee St. Louis, MD, UC San Diego
 
Michelle Don, MD, UC San Diego


__TOC__
__TOC__
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==Cancer Category / Type==
==Cancer Category / Type==


Lymphoproliferative disorder (provisional entity)<ref name=":0">Villamor N, et al., (2017). Chronic lymphoproliferative disorder of NK cells, 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 3351-352</ref>
Mature T-cell and NK-cell neoplasms <ref name=":0">1.     Morice WG, Cheng CL, Loughran TP Jr., et al. NK-large granular lymphocytic leukaemia. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. Lyon (France): International Agency for Research on Cancer; Forthcoming 2024. (WHO classification of tumours series, 5th ed.; vol. 11). <nowiki>https://publications.iarc.who.int/</nowiki>.</ref>


==Cancer Sub-Classification / Subtype==
==Cancer Sub-Classification / Subtype==


Put your text here
None <ref name=":0" />


==Definition / Description of Disease==
==Definition / Description of Disease==
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.




*Persistent (>6 months) increase in peripheral blood NK-cell count without a clearly identifiable cause
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" />
*NK-cell count usually >2x10<sup>9</sup>/L
*Indolent


==Synonyms / Terminology==


<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.}}<ref name=":0" /></blockquote>
* Chronic lymphoproliferative disorder of NK cells
==Synonyms / Terminology==


* Chronic NK-large granular lymphocyte lymphoproliferative disorder


*Chronic NK-lymphocytosis
* Chronic NK-cell lymphocytosis (historical)
*Chronic NK large granular lymphocyte lymphoproliferative disorder
*Indolent large granular NK-cell lymphoproliferative disorder


* Indolent leukemia of NK cells (historical) <ref name=":0" />


<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.}}<ref name=":0" /></blockquote>
==Epidemiology / Prevalence==
==Epidemiology / Prevalence==


* Median age: 60 years


*Adults (median age 60 years old)
* Does not show sex, racial, geographical, or genetic predisposition <ref name=":0" />
*No known racial or genetic predisposition
 


<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.}}<ref name=":0" /></blockquote>
==Clinical Features==
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|'''Signs and Symptoms'''
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
|Asymptomatic (incidental finding on complete blood counts)
 
May occur in association with autoimmune disorders, solid tumors, hematological neoplasms, and neuropathy
EXAMPLE B-symptoms (weight loss, fever, night sweats)


EXAMPLE Fatigue
Uncommon/atypical: splenomegaly, hepatomegaly, lymphadenopathy, skin involvement <ref name=":0" />
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
|'''Laboratory Findings'''
|EXAMPLE Cytopenias
|Lymphocytosis, variable neutropenia and/or anemia <ref name=":0" />
 
EXAMPLE Lymphocytosis (low level)
|}
|}


==Sites of Involvement==
==Sites of Involvement==


* Peripheral blood and bone marrow


*Peripheral blood
* Uncommon: spleen <ref name=":0" />
*Bone marrow
 


<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.}}<ref name=":0" /></blockquote>
==Morphologic Features==
==Morphologic Features==


* NK-cells are typically intermediate to large in size with small, round nuclei and moderate cytoplasm with fine or coarse azurophilic granules.


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


<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.}}<ref name=":0" /></blockquote>
==Immunophenotype <ref name=":0" />==
==Immunophenotype==
 
 
<br />


{| class="wikitable sortable"
{| class="wikitable sortable"
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|Positive||cytoplasmic CD3-epsilon
|Positive||cytoplasmic CD3-epsilon
|-
|-
|Positive (frequent)||weak CD56
|Positive (frequent)||CD56
|-
|-
|Positive||Cytotoxic markers  
|Positive||Cytotoxic markers  
Line 117: Line 101:
|Negative
|Negative
|EBV
|EBV
|}<br />
|}
 
<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.}}<ref name=":0" /></blockquote>
==Chromosomal Rearrangements (Gene Fusions)==
==Chromosomal Rearrangements (Gene Fusions)==
None


Put your text here and fill in the table
==Individual Region Genomic Gain / Loss / LOH==


{| class="wikitable sortable"
None
|-
==Characteristic Chromosomal Patterns==
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference)
|Yes
|No
|Yes
|EXAMPLE


The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
None
|}
==Gene Mutations (SNV / INDEL)==
 
 
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}
 
* Presence of STAT mutations could imply therapeutic targets
 
</blockquote>
==Individual Region Genomic Gain / Loss / LOH==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!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)
!Notes
!Notes
|-
|-
|EXAMPLE
|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>
 
|
7
|Variable: 9% <ref>{{Cite journal|last=Gasparini|first=Vanessa Rebecca|last2=Binatti|first2=Andrea|last3=Coppe|first3=Alessandro|last4=Teramo|first4=Antonella|last5=Vicenzetto|first5=Cristina|last6=Calabretto|first6=Giulia|last7=Barilà|first7=Gregorio|last8=Barizza|first8=Annica|last9=Giussani|first9=Edoardo|date=2020-04-22|title=A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells|url=https://pubmed.ncbi.nlm.nih.gov/32321919|journal=Blood Cancer Journal|volume=10|issue=4|pages=42|doi=10.1038/s41408-020-0309-2|issn=2044-5385|pmc=7176632|pmid=32321919}}</ref> to 30% <ref name=":2">{{Cite journal|last=Jerez|first=Andres|last2=Clemente|first2=Michael J.|last3=Makishima|first3=Hideki|last4=Koskela|first4=Hanna|last5=Leblanc|first5=Francis|last6=Peng Ng|first6=Kwok|last7=Olson|first7=Thomas|last8=Przychodzen|first8=Bartlomiej|last9=Afable|first9=Manuel|date=2012-10-11|title=STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia|url=https://pubmed.ncbi.nlm.nih.gov/22859607|journal=Blood|volume=120|issue=15|pages=3048–3057|doi=10.1182/blood-2012-06-435297|issn=1528-0020|pmc=3471515|pmid=22859607}}</ref>
|EXAMPLE Loss
|
|EXAMPLE
|
 
chr7:1- 159,335,973 [hg38]
|EXAMPLE
 
chr7
|Yes
|Yes
|Higher frequency of symptomatic disease; no difference in overall survival <ref name=":2" />
|No current approved therapeutic targets <ref name=":1" />
| - Also seen in T-LGL <ref name=":2" />
- 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> <br />
|-
|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>
|Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation <ref name=":4" />
|28% <ref name=":5">{{Cite journal|last=Olson|first=Thomas L.|last2=Cheon|first2=HeeJin|last3=Xing|first3=Jeffrey C.|last4=Olson|first4=Kristine C.|last5=Paila|first5=Umadevi|last6=Hamele|first6=Cait E.|last7=Neelamraju|first7=Yaseswini|last8=Shemo|first8=Bryna C.|last9=Schmachtenberg|first9=Matt|date=2021-08-26|title=Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias|url=https://pubmed.ncbi.nlm.nih.gov/33786584|journal=Blood|volume=138|issue=8|pages=662–673|doi=10.1182/blood.2020005831|issn=1528-0020|pmc=8394905|pmid=33786584}}</ref> - 34% <ref name=":4" />
|STAT3 <ref name=":4" />
|
|Yes
|Yes
|No
|Unknown
|EXAMPLE
|Resistance to immunosuppressive agents have been observed; no current therapeutic target <ref name=":5" />
| - Also seen in T-LGL
- Commonly associated with CD16 low phenotype


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 reference).
- Associated with thrombocytopenia <ref name=":4" />
|-
|-
|EXAMPLE
|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>
 
|
8
|21.5% <ref name=":6" />
|EXAMPLE Gain
|
|EXAMPLE
|
 
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
|No
|No
|No
|No
|No
|No
|EXAMPLE
| - Specific to NK-LGL <ref name=":3" />
 
Common recurrent secondary finding for t(8;21) (add reference).
|}
==Characteristic Chromosomal Patterns==
 
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')</span>
 
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
|TNFAIP3; loss of function <ref name=":4" />
!Diagnostic Significance (Yes, No or Unknown)
|TSG
!Prognostic Significance (Yes, No or Unknown)
|6% <ref>{{Cite journal|last=Kawakami|first=Toru|last2=Sekiguchi|first2=Nodoka|last3=Kobayashi|first3=Jun|last4=Yamane|first4=Taku|last5=Nishina|first5=Sayaka|last6=Sakai|first6=Hitoshi|last7=Hirabayashi|first7=Yukio|last8=Nakazawa|first8=Hideyuki|last9=Ishida|first9=Fumihiro|date=2019-05|title=STAT3 mutations in natural killer cells are associated with cytopenia in patients with chronic lymphoproliferative disorder of natural killer cells|url=https://pubmed.ncbi.nlm.nih.gov/30859397|journal=International Journal of Hematology|volume=109|issue=5|pages=563–571|doi=10.1007/s12185-019-02625-x|issn=1865-3774|pmid=30859397}}</ref> - 10% <ref name=":4" />
!Therapeutic Significance (Yes, No or Unknown)
|
!Notes
|
|-
|No
|EXAMPLE
 
Co-deletion of 1p and 18q
|Yes
|No
|No
|No
|No
|EXAMPLE:
|
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
==Gene Mutations (SNV / INDEL)==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'') </span>
 
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
|PI3K pathway genes; PIK3CD activating mutation, PIK3AP1 mutation not previously described <ref name=":5" />
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|EXAMPLE: TP53; Variable LOF mutations
 
EXAMPLE:
 
EGFR; Exon 20 mutations
 
EXAMPLE: BRAF; Activating mutations
|EXAMPLE: TSG
|EXAMPLE: 20% (COSMIC)
 
EXAMPLE: 30% (add Reference)
|EXAMPLE: IDH1 R123H
|EXAMPLE: EGFR amplification
|
|
|3 patients (5%) <ref name=":5" />
|
|
|
|
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
|No
<br />
|No
|}
|No
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.
|PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome <ref name=":5" />
 
 
<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
 
Put your text here and/or fill in the tables
 
{| class="wikitable sortable"
|-
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence
|STAT5b; exon 16 missense N642H mutation in the SH2 domain, driver mutation <ref name=":1" />
!Additional information
|-
|STAT3||
* exons 12-21
 
* encoding the Src homology 2 (SH2) domain
|EXAMPLE Tumor Suppressor||Driver mutation<ref name=":1" />||variable: 9%<ref>{{Cite journal|last=Gasparini|first=Vanessa Rebecca|last2=Binatti|first2=Andrea|last3=Coppe|first3=Alessandro|last4=Teramo|first4=Antonella|last5=Vicenzetto|first5=Cristina|last6=Calabretto|first6=Giulia|last7=Barilà|first7=Gregorio|last8=Barizza|first8=Annica|last9=Giussani|first9=Edoardo|date=04 22, 2020|title=A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells|url=https://pubmed.ncbi.nlm.nih.gov/32321919|journal=Blood Cancer Journal|volume=10|issue=4|pages=42|doi=10.1038/s41408-020-0309-2|issn=2044-5385|pmc=7176632|pmid=32321919}}</ref> to 30%<ref>{{Cite journal|last=Jerez|first=Andres|last2=Clemente|first2=Michael J.|last3=Makishima|first3=Hideki|last4=Koskela|first4=Hanna|last5=Leblanc|first5=Francis|last6=Peng Ng|first6=Kwok|last7=Olson|first7=Thomas|last8=Przychodzen|first8=Bartlomiej|last9=Afable|first9=Manuel|date=2012-10-11|title=STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia|url=https://pubmed.ncbi.nlm.nih.gov/22859607|journal=Blood|volume=120|issue=15|pages=3048–3057|doi=10.1182/blood-2012-06-435297|issn=1528-0020|pmc=3471515|pmid=22859607}}</ref>
|
|
|-
|1 patient <ref name=":1" />
|STAT5b<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>
|
|
* Exon 16
* Missense N642H mutation in the SH2 domain<ref name=":1" />
|
|
|Driver mutation<ref name=":1" />
|Unknown
|1 patient<ref name=":1" />
|Unknown; progressed to aggressive disease and died due to disease <ref name=":1" />
|No current approved therapeutic targets <ref name=":1" />
|
|
*Progressed to aggressive disease<ref name=":1" />
|}
===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||EXAMPLE IDH1 R123H
|-
|Secondary Mutations||EXAMPLE Trisomy 7
|-
|Mutually Exclusive||EXAMPLE EGFR Amplification
|}
|}
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.


</blockquote>
==Epigenomic Alterations==
==Epigenomic Alterations==


Put your text here
* 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==


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
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" />
{| class="wikitable sortable"
==Genetic Diagnostic Testing Methods==
|-
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
* 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>.
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|EXAMPLE: MAPK signaling
|EXAMPLE: Increased cell growth and proliferation
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|EXAMPLE: Cell cycle regulation
|EXAMPLE: Unregulated cell division
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|EXAMPLE:  Histone modification, chromatin remodeling
|EXAMPLE:  Abnormal gene expression program
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
* 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" />.


* Most patients carry heavy mutational burden
* Absence of T-cell receptor gene rearrangement studies <ref name=":7" />.
*


</blockquote>
* Sanger Sequencing.
==Genetic Diagnostic Testing Methods==


Put your text here
* Whole Genome Sequencing.


==Familial Forms==
==Familial Forms==


Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
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==Additional Information==
==Additional Information==


Put your text here
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==Links==
==Links==


Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page <span style="color:#0070C0">(''Instructions: Once you have a text placeholder entered to which you want to add a link, highlight that text, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address including the "<nowiki>http://www</nowiki>." portion.'')</span>
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==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
<references />


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==Notes==
==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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
<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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
<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>.
<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:DISEASE]][[Category:Diseases N]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:Diseases N]]
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