A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells

Vanessa Rebecca Gasparini,Satu Mustjoki,Edoardo Giussani,Gregorio Barilà,Antonella Teramo,Alessandro Coppe,Giulia Calabretto,Annica Barizza,Andrea Binatti,Renato Zambello,Gianpietro Semenzato,Stefania Bortoluzzi,Cristina Vicenzetto,Monica Facco

doi:10.1038/s41408-020-0309-2

Abstract

The molecular pathogenesis of chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD‐NK) is poorly understood. Following the screening of 57 CLPD-NK patients, only five presented STAT3 mutations. WES profiling of 13 cases negative for STAT3/STAT5B mutations uncovered an average of 18 clonal, population rare and deleterious somatic variants per patient. The mutational landscape of CLPD-NK showed that most patients carry a heavy mutational burden, with major and subclonal deleterious mutations co-existing in the leukemic clone. Somatic mutations hit genes wired to cancer proliferation, survival, and migration pathways, in the first place Ras/MAPK, PI3K-AKT, in addition to JAK/STAT (PIK3R1 and PTK2). We confirmed variants with putative driver role of MAP10, MPZL1, RPS6KA1, SETD1B, TAOK2, TMEM127, and TNFRSF1A genes, and of genes linked to viral infections (DDX3X and RSF1) and DNA repair (PAXIP1). A truncating mutation of the epigenetic regulator TET2 and a variant likely abrogating PIK3R1-negative regulatory activity were validated. This study significantly furthered the view of the genes and pathways involved in CLPD-NK, indicated similarities with aggressive diseases of NK cells and detected mutated genes targetable by approved drugs, being a step forward to personalized precision medicine for CLPD-NK patients.

Highlights

Among the abnormal proliferations of large granular lymphocytes (LGL), chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD‐NK) is characterized by a persistent (>6 months) clonal expansion of LGL of the NK lineage[1] in the peripheral blood with an absolute NKLGL count ≥0.5 × 109/L
STAT3 and STAT5B mutations are rare in CLPD-NK patients The collected study group of 57 CLPD-NK patients (Supplementary Table 2) included the 25 cases previously screened for STAT3 exon 21 and STAT5B exon 16 mutations[16]
This study disclosed the molecular landscape of somatic mutations in CLPD‐NK by an exploration of the largest so far patient cohort analyzed by WES

Summary

Introduction

Among the abnormal proliferations of large granular lymphocytes (LGL), chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD‐NK) is characterized by a persistent (>6 months) clonal expansion of LGL of the NK lineage[1] in the peripheral blood with an absolute NKLGL count ≥0.5 × 109/L. In ANKL and NKTCL, JAK2 and STAT3 mutations, lesions of epigenetic modifiers and tumor suppressors were detected[11,12,13]. CLPD-NK patients with STAT3 mutations often require treatment and STAT3 mutations have been found to correlate with a CD3− CD16+ CD56dim CD57− immunophenotype[16] and cytopenias, such as anemia[15] or severe neutropenia[16]. STAT5B, a gene essential for NK cell biology[17] and frequently mutated in CD4+ T-LGL leukemia[18], has been found mutated only in one patient diagnosed with CLPD-NK (3%), who later progressed to ANKL9. Somatic mutations in few other genes of the JAK/ STAT pathway, such as JAK3 (10%)[14], and of the NFkappa B signaling pathway, such as TNFAIP3 (6%)[15], were seldom detected in CLPD-NK

Methods

Results

Conclusion