AimsSpliceosome genes (SF3B1, SRSF2, U2AF1 and ZRSR2) are commonly mutated in myeloid neoplasms, particularly in myelodysplastic syndromes (MDS). JAK2, MPL and CALR mutations are associated with myeloproliferative neoplasms (MPN). Although SF3B1 and MPN-associated mutations frequently co-occur in the rare entity MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), myeloid neoplasms with concurrent spliceosome and MPN-associated mutations encompass many disease entities and are not well characterised.MethodsSpecimens from 2016 to 2019 with concurrent spliceosome and MPN-associated mutations were identified, and the clinicopathologic features were assessed.ResultsThe 36 cases were divided into mutational categories based on their spliceosome mutation. At diagnosis, cases with concurrent U2AF1 and MPN-associated mutations had lower leucocyte counts and platelet counts than did the other groups. Cases with mutant SRSF2 were more likely to have ASXL1 and IDH2 mutations, while U2AF1-mutated neoplasms were more likely to have an abnormal karyotype. The most common SF3B1 K700 and U2AF1 S34 mutational hotspots were underrepresented in our cohort of myeloid neoplasms with concurrent spliceosome and MPN-associated mutations, as SF3B1 and U2AF1 mutations tended to involve other codons. Numerous WHO-defined disease entities were represented in each spliceosome gene category; although MDS/MPN-RS-T were only identified in the group with SF3B1 mutations, they constituted only 1/4 of the neoplasms in the category.ConclusionsMyeloid neoplasms with different mutant splicing factor and concurrent MPN-associated mutations demonstrate somewhat different clinical and pathologic features, but t he association between genotypes and phenotypes in these overlapping neoplasms is not straightforward.

Objectives Hypocellular acute myeloid leukemia (AML) is uncommon. Despite the prognostic and therapeutic importance of mutational analysis, the mutational landscape of hypocellular AML is not well understood. Methods We identified 25 patients with hypocellular AML, and 141 patients with nonhypocellular AML were identified as a control group. We applied next-generation sequencing for the first time to profile this entity. Results The hypocellular AML patients were older than those with nonhypocellular AML (P = .037). At diagnosis, hypocellular AML had lower leukocyte counts (P = .012), higher hemoglobin (P = .003), and lower blast counts in the peripheral blood (P < .001) and bone marrow (P = .003). Hypocellular AML was less likely to have mutations involving cell proliferation (P = .027) and NPM1 (P = .022) compared with nonhypocellular AML. Hypocellular AML showed a high incidence of spliceosomal mutations and myelodysplastic syndrome-defining chromosome abnormalities (65%), but the incidence was not significantly different from that in nonhypocellular AML. There was no significant survival difference between hypocellular and nonhypocellular AML. Conclusions To our knowledge, this study is the first to demonstrate hypocellular AML showed fewer genetic alterations involving cell proliferation and NPM1 when compared directly with nonhypocellular AML; this finding likely contributes to the low marrow cellularity in at least a portion of the patients with hypocellular AML.

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