Compendium of Cancer Genome Aberrations

HAEM5:NK-large granular lymphocytic leukaemia

Revision as of 21:50, 6 January 2026 by Sumire.Kitahara (talk | contribs)
A checked version of this page, approved on 6 January 2026, was based on this revision.

Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Hailee St. Louis, MD, UC San Diego

Michelle Don, MD, UC San Diego

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category T-cell and NK-cell lymphoid proliferations and lymphomas
Family Mature T-cell and NK-cell neoplasms
Type Mature T-cell and NK-cell leukaemias
Subtype(s) NK-large granular lymphocytic leukaemia

Related Terminology

Acceptable Chronic lymphoproliferative disorder of NK cells; chronic NK-large granular lymphocyte lymphoproliferative disorder
Not Recommended Chronic NK-cell lymphocytosis; indolent leukaemia of NK cells

Gene Rearrangements

None

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
N/A N/A N/A N/A N/A N/A N/A N/A

Individual Region Genomic Gain/Loss/LOH

None

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
N/A N/A N/A N/A N/A N/A N/A

Characteristic Chromosomal or Other Global Mutational Patterns

None

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
N/A N/A N/A N/A N/A N/A

Gene Mutations (SNV/INDEL)

Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other 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
STAT3 Exons 12-21 encoding the Src homology 2 (SH2 domain on two hotspots: D661 and Y640), driver mutation [1] Variable: 9% [2] to 30% [3]

(NK-LGL)

D,P Yes (NCCN) No current approved therapeutic targets [1]

Higher frequency of symptomatic disease; no difference in overall survival [3] Also seen in T-LGL [3] Commonly associated  with CD16high/CD57low or cytotoxic memory NK-LGL's [4]

TET2 Loss of function [5] Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation [5] Common: 28% [6] - 34% [5]

(NK-LGL)

D Yes (NCCN) Resistance to immunosuppressive agents have been observed; no current therapeutic target [6]

Also seen in T-LGL Commonly associated with CD16 low phenotype Associated with thrombocytopenia [5]

CCL22 Gain of function [7] Common: 21.5% [7]

(NK-LGL)

No Specific to NK-LGL [4]
TNFAIP3 Loss of function [5] TSG Recurrent: 6% [8] - 10% [5]

(NK-LGL)

No
PI3K pathway genes PIK3CD activating mutation, PIK3AP1 mutation not previously described [6] Rare: 3 patients (5%) [6]

(NK-LGL)

No PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome [6]
STAT5b Exon 16 missense N642H mutation in the SH2 domain, driver mutation [1] Rare: 1 patient [1] No Progressed to aggressive disease and died due to disease [1]

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

TET2 shows increased methylated regions in clonal NK-LGLs compared to normal NK-cells [6]

Genes and Main Pathways Involved

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 [9]
TET2; loss of function mutations DNA methylation/epigenetic regulation DNA methylation alters NK cell gene expression[10]
CCL22; gain of function mutations Chemokine signaling and microenvironmental interaction Alters NK cell interaction with the microenvironment, contributing to clonal dominance and unique immunophenotype [7]
TNFAIP3; inactivating alterations NF-κB negative regulation Loss of negative regulation enhances NF-κB signaling, promoting cell survival and anti-apoptotic transcription[5]
KRAS, NOTCH1 PTEN; PIK3R1, PIK3CD, PIK3AP1 RAS/MAPK and Pi3K/AKT pathways Dysregulation of the balance between survival and apoptosis [2][4]

Genetic Diagnostic Testing Methods

  • Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality [11].
  • Mutational screen for STAT3, STAT5b, TET2, TNFAIP3 and CCL22 mutations may be more helpful when compared to KIR analysis on diagnostic work-up [4].
  • Absence of T-cell receptor gene rearrangements by PCR[11].
  • Sanger Sequencing.
  • Whole Genome Sequencing.

Familial Forms

None

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.

Epidemiology/prevalence: Median age: 60 years; does not show sex, racial, geographical, or genetic predisposition[12]

Clinical features:

  • 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[12]
  • Laboratory findings - Lymphocytosis, variable neutropenia and/or anemia[12]

Sites of involvement: Peripheral blood and bone marrow; uncommonly spleen[12]

Morphologic features: 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.[12]

Immunophenotype:

Positive - CD16, CD56 (frequent), 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)

Negative - surface CD3, EBV

Links

N/A

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Rajala, Hanna L. M.; et al. (2013-05-30). "Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia". Blood. 121 (22): 4541–4550. doi:10.1182/blood-2012-12-474577. ISSN 1528-0020. PMC 3668487. PMID 23596048.
  2. ↑ 2.0 2.1 Gasparini, Vanessa Rebecca; et al. (2020-04-22). "A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells". Blood Cancer Journal. 10 (4): 42. doi:10.1038/s41408-020-0309-2. ISSN 2044-5385. PMC 7176632 Check |pmc= value (help). PMID 32321919 Check |pmid= value (help).
  3. ↑ 3.0 3.1 3.2 Jerez, Andres; et al. (2012-10-11). "STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia". Blood. 120 (15): 3048–3057. doi:10.1182/blood-2012-06-435297. ISSN 1528-0020. PMC 3471515. PMID 22859607.
  4. ↑ 4.0 4.1 4.2 4.3 Drillet, Gaëlle; et al. (2022). "Toward a Better Classification System for NK-LGL Disorders". Frontiers in Oncology. 12: 821382. doi:10.3389/fonc.2022.821382. ISSN 2234-943X. PMC 8843930 Check |pmc= value (help). PMID 35178350 Check |pmid= value (help).
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Pastoret, Cédric; et al. (2021-06-10). "Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells". Blood. 137 (23): 3237–3250. doi:10.1182/blood.2020006721. ISSN 1528-0020. PMC 8351897 Check |pmc= value (help). PMID 33512451 Check |pmid= value (help).
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Olson, Thomas L.; et al. (2021-08-26). "Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias". Blood. 138 (8): 662–673. doi:10.1182/blood.2020005831. ISSN 1528-0020. PMC 8394905 Check |pmc= value (help). PMID 33786584 Check |pmid= value (help).
  7. ↑ 7.0 7.1 7.2 Baer, Constance; et al. (2022-05). "CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk". Nature Genetics. 54 (5): 637–648. doi:10.1038/s41588-022-01059-2. ISSN 1546-1718. PMC 9117519 Check |pmc= value (help). PMID 35513723 Check |pmid= value (help). Check date values in: |date= (help)
  8. ↑ Kawakami, Toru; et al. (2019-05). "STAT3 mutations in natural killer cells are associated with cytopenia in patients with chronic lymphoproliferative disorder of natural killer cells". International Journal of Hematology. 109 (5): 563–571. doi:10.1007/s12185-019-02625-x. ISSN 1865-3774. PMID 30859397. Check date values in: |date= (help)
  9. ↑ Marchand, Tony; et al. (2024-10-31). "A modern view of LGL leukemia". Blood. 144 (18): 1910–1923. doi:10.1182/blood.2023021790. ISSN 1528-0020. PMID 38848524 Check |pmid= value (help).
  10. ↑ Semenzato, Gianpietro; et al. (2025-06). "NK-type large granular lymphocyte leukemia comes of age". HemaSphere. 9 (6): e70161. doi:10.1002/hem3.70161. ISSN 2572-9241. PMC 12194722 Check |pmc= value (help). PMID 40568352 Check |pmid= value (help). Check date values in: |date= (help)
  11. ↑ 11.0 11.1 Lamy, Thierry; et al. (2017-03-02). "LGL leukemia: from pathogenesis to treatment". Blood. 129 (9): 1082–1094. doi:10.1182/blood-2016-08-692590. ISSN 1528-0020. PMID 28115367.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 WHO Classification of Tumours Editorial Board, eds, WHO Classification of Tumours, Haematolymphoid Tumours Part A. 5th edition, IARC Press:Lyon, 2024.


Notes

*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 Associate Editor 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):


*Citation of this Page: “NK-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 01/6/2026, https://ccga.io/index.php/HAEM5:NK-large_granular_lymphocytic_leukaemia.

Retrieved from "https://test.ccga.io/index.php?title=HAEM5:NK-large_granular_lymphocytic_leukaemia&oldid=20023"