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

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.

Fig. 1. STAT3 mutations in a cohort of 57 CLPD-NK patients.

a STAT3 was mutated in 5 out of 57 patients (9%). b Four different variants were observed in the SH2 domain.

Fig. 2. Heterogeneity of CLPD-NK patient leukemic clones disclosed multiple clonal and subclonal somatic mutations.

a Number of mutations per patient and b summary of genes recurrently mutated in the cohort, showing different classes of VAF; c prominent genes in each patient are indicated by radar plots of VAF (only genes with somatic variants with VAF ≥ 0.1 are shown).

Fig. 3. Summary of most relevant genes somatically mutated in CLPD-NK: functions and putative drivers.

a KEGG and Reactome pathway-derived network of somatic mutations detected in CLPD-NK, by WES (circles) and by STAT3 targeted screening (triangle); direct, indirect and predicted relations between genes and gene products annotated in pathways topologies are shown; node colors indicate different groups of pathways and functions, according to the table in panel (b); circular node size is proportional to the evaluation of possible driver role considering mutation VAF and predicted impact and gene function and expression; b Genes involved in different groups of pathways mutated in each patient highlight functions recurrently hit in different patients (gene name in bold, VAF ≥ 0.1; bold and underlined VAF ≥ 0.2).