Age-associated clonal hematopoiesis caused by acquired mutations in myeloid cancer-associated genes is highly prevalent in the normal population. Its etiology, biological impact on hematopoiesis, and oncogenic risk is poorly defined at this time. To gain insight into this phenomenon, we analyzed a cohort of 2530 related and unrelated hematologically normal individuals (ages 55 to 101 years). We used a sensitive gene-targeted deep sequencing approach to gain precision on the exact prevalence of driver mutations and the proportions of affected genes. Mutational status was correlated with biological parameters. We report a higher overall prevalence of driver mutations (13.7%), which occurred mostly (93%) in or and were highly age-correlated. Mutation in these 2 genes had some distinctive effects on end points. mutations were more age-dependent, associated with a modest neutropenic effect (9%, = .012), demonstrated familial aggregation, and associated with chronic obstructive pulmonary disease. Mutations in had no impact on blood counts or indices. Mutational burden of both genes correlated with X-inactivation skewing but no significant association with age-adjusted telomere length reduction was documented. The discordance between the high prevalence of mutations in these 2 genes and their limited biological impact raise the question of the potential role of dysregulated epigenetic modifiers in normal aging hematopoiesis, which may include support to failing hematopoiesis.

Survival prediction in essential thrombocythaemia (ET) and polycythaemia vera (PV) is currently based on clinically-derived variables; we examined the possibility of integrating genetic information for predicting survival. To this end, 906 molecularly-annotated patients (416 Mayo Clinic; 490 University of Florence, Italy), including 502 ET and 404 PV, were recruited. Multivariable analysis identified spliceosome mutations to adversely affect overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis-free (U2AF1, SF3B1 in ET) survival; TP53 mutations predicted leukaemic transformation in ET; "adverse" mutations occurred in 51 (10%) ET and 8 (2%) PV patients. We confirmed the independent survival effect of adverse mutations [hazard ratio (HR) 2Á4, 95% CI 1Á6-3Á5], age >60 years (6Á6, 4Á6-9Á7), male sex (1Á8, 1Á3-2Á4) and leukocytosis ≥11 9 10 9 /l (1Á6, 1Á1-2Á2), in ET, and adverse mutations (7Á8, 3Á1-17Á0), age >67 years (5Á4, 3Á6-8Á1), leukocytosis ≥15 9 10 9 /l (2Á8, 1Á8-4Á2) and thrombosis history (2Á0, 1Á4-2Á9), in PV. HR-based risk point allocation allowed development of three-tiered mutation-enhanced international prognostic systems (MIPSS) which were validated in both cohorts and performance was shown to be superior to conventional scoring systems. Spliceosome mutations enhance survival prediction in ET and PV and identify patients at risk for fibrotic progression. TP53 mutations predict leukaemic transformation in ET.

Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm-relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was 57%, 20%, 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were 47%, 19%, 17%, 16%, 15%, and 13%; relative mutual exclusivity was expressed by, ,, ,, and mutations. Paired chronic-blast phase sample analysis was possible in 19 patients and revealed more frequent blast phase acquisition of, ,, ,, and mutations/variants. In multivariable analysis, and mutations/variants were associated with shorter survival duration; respective hazard ratios (HRs) (95% confidence interval [CI]) were 2.1 (95% CI, 1.1-3.8) and 3.0 (95% CI, 1.1-6.6). An all-inclusive multivariable analysis confirmed the prognostic relevance of mutations (HR, 1.9; 95% CI, 1.5-5.5) and also showed additional contribution from a treatment strategy that includes transplant or induction of complete or near-complete remission (HR, 0.3; 95% CI, 0.2-0.5). The current study points to specific mutations that might bear pathogenetic relevance for leukemic transformation in MPN and also suggest an adverse survival effect of mutations.