International Journal of Hematology

DOI: 10.1007/s12185-019-02625-x Pages: 563-571

STAT3 mutations in natural killer cells are associated with cytopenia in patients with chronic lymphoproliferative disorder of natural killer cells

1. Shinshu University School of Medicine, Division of Hematology, Department of Internal Medicine

2. Shinshu University School of Medicine, Department of Comprehensive Cancer Therapy

3. Shinshu University, Department of Health and Medical Sciences, Graduate School of Medicine

4. Nagano Children’s Hospital, Department of Laboratory Medicine

5. Shinshu University School of Medicine, Department of Biomedical Laboratory Sciences

6. Matsumoto Medical Center Masumoto Hospital, Division of Hematology

Correspondence to:
Fumihiro Ishida
Tel: +81-263-37-2391



Chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) is a rare disease with an indolent clinical course, which is characterized by persistent increase in large granular lymphocytes of NK-cell type. A somatic mutation in signal transducer and activator transcription 3 (STAT3) has been reported in patients with CLPD-NK; however, the details of the mutational profiles and their clinical significance remain unclear. We performed mutation analyses of the STAT3, STAT5B, and TNF-alpha-induced protein 3 (TNFAIP3) genes for mononuclear cell-derived DNA in 17 CLPD-NK patients using allele-specific polymerase chain reaction and amplicon sequencing. Mutations in STAT3 and TNFAIP3 were found in 29% (5/17) and 6% (1/17) of cases, respectively. All patients were negative for STAT5B mutations. In all three STAT3-mutation (+) patients studied, STAT3 mutations were restricted to sorted NK cells. STAT3 mutation (+) patients had a lower hemoglobin level (6.6 g/dL vs. 13.9 g/dL, P = 0.0044) and showed a trend toward reduced neutrophil counts (1.22 × 109/L vs. 3.10 × 109/L, P = 0.070) compared with the STAT3 mutation (−) patients. No mutations in these genes were found in patients with neuropathy. These results suggest that heterogeneity of CLPD-NK and STAT3-mutated NK cells may play a significant role in cytopenia in CLPD-NK patients.

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