Frequent Somatic TET2 Mutations in Chronic NK-LGL Leukemia with Distinct Patterns of Cytopenias.

Chronic natural killer large granular lymphocyte (NK-LGL) leukemia, also referred to as chronic lymphoproliferative disorder of NK cells (CLPD-NK), is a rare disorder defined by prolonged expansion of clonal NK cells. Similar prevalence of STAT3 mutations in chronic T- and NK-LGL leukemia is suggestive of common pathogenesis. We undertook whole genome sequencing to identify mutations unique to NK-LGL leukemia. We analyzed the results to develop a resequencing panel and applied it to 58 patients. PI3K pathway gene mutations (PIK3CD/PIK3AP1) and TNFAIP3 mutations were seen in 5% and 10% of patients, respectively. TET2 was exceptional in that mutations were present in 16/58 (28%) of patient samples, with evidence that TET2 mutations can be dominant and exclusive to the NK compartment. Reduced-representation bisulfite sequencing (RRBS) demonstrated that methylation patterns were significantly altered in TET2-mutant samples. The promoter of TET2 and that of PTPRD, a negative regulator of STAT3, were found to be methylated in additional cohort samples, largely confined to the TET2 mutant group. Mutations in STAT3 were observed in 19/58 (33%) of patient samples, seven of which had concurrent TET2 mutations. Thrombocytopenia and resistance to immunosuppressives were uniquely observed in those patients with only TET2 mutation (Games-Howell p=0.0074, Fisher's exact p=0.00466, respectively). Patients with STAT3 mutation, inclusive of those with TET2 co-mutation, had lower hematocrit (HCT), hemoglobin (HGB), and absolute neutrophil count (ANC) compared to STAT3 wild-type patients (Welch's t-test, p<=0.015). We present the discovery of TET2 mutations in chronic NK-LGL leukemia and evidence that it identifies a unique molecular subtype.