Aggressive NK-cell Leukemia

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Primary Author(s)*

Shanelle De Lancy, MD, Shashirekha Shetty, PhD

Cancer Category/Type

Mature T- and NK-cell neoplasms

Cancer Sub-Classification / Subtype

Aggressive NK-cell Leukaemia

Definition / Description of Disease

  • Proliferation of NK-cells
  • Associated with EBV infection, but EBV may be negative in a subset of patients
  • Aggressive clinical course with poor response to chemotherapy
  • Relapse common in patients that achieve complete remission (+/- bone marrow transplantation)

Synonyms / Terminology

Aggressive NK-cell leukaemia/lymphoma

Epidemiology / Prevalence[1]

  • Young to middle-aged adults
  • Median age: 40 years; Peaks in 3rd and 5th decades
  • More prevalent in Asian, Central and South America[2]
  • No gender predilection
  • EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations[3]
  • Median survival: <2 months

Clinical Features[1][4]

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

*EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells

Sites of Involvement[5]

  • Peripheral blood
  • Bone marrow
  • Liver
  • Spleen
  • Lymph nodes

but may involve any organ including skin, lungs, soft tissue and omentum

Morphologic Features[1]

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

Bone Marrow:

  • Interstitial or intrasinusoidal infiltrating pattern, which may be extensive, focal or subtle[2]
  • May have interspersed reactive histiocytes with haemophagocytosis


  • 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


Finding Marker
Positive (universal) CD2, CD3-epsilon, CD56, CD94, cytotoxic molecules (TIA1, Granzyme B, perforin A), FASL, c-MYC
Positive (subset) CD16 (75%), CD11b, EBER, p53, pSTAT3, PD-L1, BCL2
Negative (universal) surface CD3, CD4, CD5, CD57 (usually), CD158a/b/e, TCR alpha/beta, TCR gamma/delta
Negative (subset) CD7, CD45

Chromosomal Rearrangements (Gene Fusions)


Characteristic Chromosomal Aberrations / Patterns[3]

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.

Genomic Gain/Loss/LOH[2][1]

Chromosome Gain/Loss/Amp/LOH
1q23.1-q23.2 Gain
1q31.3-q44 Gain
7p15.1-q22.3 Loss
17p13.1 Loss

Gene Mutations (SNV/INDEL)[3][6][7]

Gene Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence [3]
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


  • Mutations in the JAK-STAT pathway appear to be mutually exclusive[7]
  • 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

Epigenomics (Methylation)[3][7]

Mutations seen in epigenetic regulatory molecules:

  • RNA helicase DDX3X (28%)
  • TET2 (28%)
  • CREBBP (21%)
  • MLL2 (21%)

Genes and Main Pathways Involved[3]

  • Upregulated JAK/STAT-MYC biosynthesis axis due to upstream STAT3 activation of the MYC transcription program. *
  • Alterations in RAS-MAPK pathway also identified
  • Epigenetic modifier genes (e.g BCOR, KMT2D/MLL2, SETD2, PRDM9, CREBBP, and TET2)
  • DNA damage repair (TP53, ASXL1, ASXL2, BRINP3)
  • mRNA splicing factors (PRPF40B)

*Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.

Diagnostic Testing Methods[2]

Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)[8]

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:

  • Heat shock protein 90 (HSP90) inhibitors
  • Polo-like kinase (PLK) inhibitors
  • Aurora kinase (AURK) inhibitors
  • Cyclin-dependent kinase inhibitors
  • Histone deacetylase inhibitors

Familial Forms


Other Information



Extranodal NK/T-cell lymphoma

Hepatosplenic T-cell Lymphoma (HSTCL)

Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK)


  1. 1.0 1.1 1.2 1.3 1.4 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.
  2. 2.0 2.1 2.2 2.3 2.4 El Hussein, Siba; et al. (09 2020). "Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia". The American Journal of Surgical Pathology. 44 (9): 1235–1243. doi:10.1097/PAS.0000000000001518. ISSN 1532-0979. PMID 32590457 Check |pmid= value (help). Check date values in: |date= (help)
  3. 3.0 3.1 3.2 3.3 3.4 3.5 El Hussein, Siba; et al. (10 09, 2020). "Aggressive NK Cell Leukemia: Current State of the Art". Cancers. 12 (10). doi:10.3390/cancers12102900. ISSN 2072-6694. PMC 7600035 Check |pmc= value (help). PMID 33050313 Check |pmid= value (help). Check date values in: |date= (help)
  4. Kim, Wook Youn; et al. (2019). "Epstein-Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases". Frontiers in Pediatrics. 7: 71. doi:10.3389/fped.2019.00071. ISSN 2296-2360. PMC 6428722. PMID 30931288.
  5. Hue, Susan Swee-Shan; et al. (2020-01). "Epstein–Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach". Pathology. 52 (1): 111–127. doi:10.1016/j.pathol.2019.09.011. Check date values in: |date= (help)
  6. Gao, Juehua; et al. (2020-11). "Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma". Human Pathology. 105: 20–30. doi:10.1016/j.humpath.2020.08.008. Check date values in: |date= (help)
  7. 7.0 7.1 7.2 Huang, Liang; et al. (2018-02). "Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia". Cell Research. 28 (2): 172–186. doi:10.1038/cr.2017.146. ISSN 1001-0602. PMC 5799812. PMID 29148541. Check date values in: |date= (help)CS1 maint: PMC format (link)
  8. Dufva, Olli; et al. (04 19, 2018). "Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target". Nature Communications. 9 (1): 1567. doi:10.1038/s41467-018-03987-2. ISSN 2041-1723. PMC 5908809. PMID 29674644. Check date values in: |date= (help)


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