Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells

• Published in: Blood Vol. 137; no. 23; pp. 3237 - 3250
• Main Authors: Pastoret, Cédric, Desmots, Fabienne, Drillet, Gaëlle, Le Gallou, Simon, Boulland, Marie-Laure, Thannberger, Alexia, Doncker, Anne-Violaine, Salaun, Véronique, Damaj, Gandhi Laurent, Veyrat-Masson, Richard, Tournilhac, Olivier, Moignet, Aline, Pangault, Céline, Roussel, Mikaël, Fest, Thierry, Lamy, Thierry
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.06.2021; American Society of Hematology
• Subjects: Cancer; chronic lymphoproliferative disorder of NK cells; Clinical Trials and Observations; Immunobiology and Immunotherapy; KIR phenotype; large granular lymphocyte leukemia; Life Sciences; Lymphoid Neoplasia; NEOPLASIA/Lymphomas and Other Lymphoproliferative Conditions: genetic and other predisposing conditions; STAT3; TET2; TET2; large granular lymphocyte leukemia; NEOPLASIA/Lymphomas and Other Lymphoproliferative Conditions: genetic and other predisposing conditions; chronic lymphoproliferative disorder of NK cells; KIR phenotype; STAT3; NK cells; chronic lymphoproliferative disorders of NK cells
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2020006721

Distinguishing chronic lymphoproliferative disorders of NK cells (CLPD-NK) from reactive NK-cell expansion is challenging. We assessed the value of killer immunoglobulin-like receptor(KIR) phenotyping and targeted high-throughput sequencing in a cohort of 114 consecutive patients with NK cell proliferation, retrospectively assigned to a CLPD-NK group (n = 46) and a reactive NK group (n = 68). We then developed an NK-cell clonality score combining flow cytometry and molecular profiling with a positive predictive value of 93%. STAT3 and TET2 mutations were respectively identified in 27% and 34% of the patients with CLPD-NK, constituting a new diagnostic hallmark for this disease. TET2-mutated CLPD-NK preferentially exhibited a CD16low phenotype, more frequently displayed a lower platelet count, and was associated with other hematologic malignancies such as myelodysplasia. To explore the mutational clonal hierarchy of CLPD-NK, we performed whole-exome sequencing of sorted, myeloid, T, and NK cells and found that TET2 mutations were shared by myeloid and NK cells in 3 of 4 cases. Thus, we hypothesized that TET2 alterations occur in early hematopoietic progenitors which could explain a potential link between CLPD-NK and myeloid malignancies. Finally, we analyzed the transcriptome by RNA sequencing of 7 CLPD-NK and evidenced 2 groups of patients. The first group displayed STAT3 mutations or SOCS3 methylation and overexpressed STAT3 target genes. The second group, including 2 TET2-mutated cases, significantly underexpressed genes known to be downregulated in angioimmunoblastic T-cell lymphoma. Our results provide new insights into the pathogenesis of NK-cell proliferative disorders and, potentially, new therapeutic opportunities. •TET2 mutations, present in 34% of chronic lymphoproliferative disorders of NK cells, are associated with CD16low phenotype.•TET2 mutations can be an early event in the pathogenesis of CLPD-NK, explaining its association with other lymphoid or myeloid malignancies. [Display omitted]