Clinicopathologic characterisation of myeloid neoplasms with concurrent spliceosome mutations and myeloproliferative-neoplasm-associated mutations

Abstract

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.

Essential thrombocythaemia with aggressive megakaryocytosis after myelofibrotic transformation

“…Although the underlying molecular mechanism is not fully elucidated, U2AF1 mutations are significantly correlated with anemia and thrombocytopenia, and are recognized as adverse factors associated with inferior overall or leukemia-free survival [17]. In addition, co-occurrence of mutation of MPN-associated driver genes (JAK2, CALR or MPL) and spliceosome genes is observed in certain myeloid malignancies [19], such as JAK2 V617F and SF3B1 mutation in MDS/MPN with ring sideroblasts and thrombosis (MDS/MPN-RS-T) [20,21]. These lines of evidence imply that the U2AF1 mutation also may have contributed to an aggressive proliferation of mature megakaryocytes at the final stage in this case.…”

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“…SRSF2 P95H expression in mouse models leads to myeloid bias, impaired B cell development and maturation, and decreased haemopoietic stem cell numbers reminiscent of human myelodysplastic syndrome (MDS) in vivo [103]. MPN with SRSF2 mutations have a high variant allele frequency, suggesting an impact on clonal dominance [104]. SRSF2 mutations are enriched in blast phase MPN (15-22%) and appear to be more common in combination with JAK2 and MPL driver mutations compared to CALR [61,62].…”