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}}</blockquote>

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<~~span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https:~~//www.genenames.org/ HUGO-approved gene names and symbols] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see [[Author_Instructions]] and [[Frequently Asked Questions (FAQs)|FAQs]] as well as contact your [[Leadership|Associate Editor]] or [mailto:CCGA@cancergenomics.org Technical Support])

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==Primary Author(s)*==

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==Synonyms / Terminology==

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* Chronic lymphoproliferative disorder of NK cells

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*Chronic lymphoproliferative disorder of NK cells

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* Chronic NK-large granular lymphocyte lymphoproliferative disorder

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*Chronic NK-large granular lymphocyte lymphoproliferative disorder

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* Chronic NK-cell lymphocytosis (historical)

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*Chronic NK-cell lymphocytosis (historical)

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

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

==Epidemiology / Prevalence==

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* Median age: 60 years

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*Median age: 60 years

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* Does not show sex, racial, geographical, or genetic predisposition <ref name=":0" />

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*Does not show sex, racial, geographical, or genetic predisposition <ref name=":0" />

==Clinical Features==

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==Sites of Involvement==

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* Peripheral blood and bone marrow

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*Peripheral blood and bone marrow

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* Uncommon: spleen <ref name=":0" />

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*Uncommon: spleen <ref name=":0" />

==Morphologic Features==

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

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

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

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

==Immunophenotype <ref name=":0" />==

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!Notes

|-

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|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>

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|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>

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|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>

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|Yes

|Unknown

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|Resistance to immunosuppressive agents have been observed; no current therapeutic target <ref name=":5" />

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|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

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==Epigenomic Alterations==

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

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

==Genes and Main Pathways Involved==

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==Genetic Diagnostic Testing Methods==

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* 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>.

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*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>.

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* 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" />.

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*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" />.

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

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

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* Sanger Sequencing.

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*Sanger Sequencing.

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* Whole Genome Sequencing.

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*Whole Genome Sequencing.

==Familial Forms==

Hailee.StLouis

2

edits

Changes

HAEM5:NK-large granular lymphocytic leukaemia (view source)

Revision as of 12:57, 4 June 2024