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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.

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