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SF3B1 mutations in primary myelofibrosis: clinical, histopathology and genetic correlates among 155 patients

Leukemia volume 26, pages 1135–1137 (2012)Cite this article

Yoshida et al.1 recently described recurrent somatic mutations that involved different components of the RNA splicing machinery and other spliceosome-related genes in 209 of 582 patients with myeloid neoplasms: 228 with myelodysplastic syndromes (MDS) with (n=73) or without (n=155) ring sideroblasts (RS), 88 with chronic myelomonocytic leukemia (CMML), 151 with primary acute myeloid leukemia (AML), 62 with AML that is therapy-related or displayed MDS-like features (t-AML/MDS) and 53 with myeloproliferative neoplasms (MPN). Mutational frequencies were ∼85% in MDS-RS, 44% in MDS without RS, 55% in CMML, 26% in t-AML/MDS, 7% in primary AML and 9% in MPN. In MDS-RS, the most frequent (75.3%) spliceosome mutations involved splicing factor 3B subunit 1 (SF3B1) with mutational frequencies of 83% in refractory anemia with RS (RARS) and 76% in refractory cytopenia with multilineage dysplasia-RS. SF3B1 mutations were less frequent in MDS without RS (6.5%) or other myeloid neoplasms (<5%); none of the MPN cases displayed SF3B1 mutations. Mutations involving the serine/arginine-rich (SR) protein, SRSF2, were more frequent in CMML (28.4%), MDS without RS (11.6%) or t-AML/MDS (6.5%). The authors also described other spliceosome component mutations that involved genes encoding for U2 auxiliary factor small nuclear ribonucleoprotein (snRNP) complexes including U2AF35 and U2AF65, zinc finger, RNA-binding motif and serine/arginine-rich (SR) protein 2 (ZRSR2), SF3A1, SF1 and PRP40 pre-mRNA processing factor 40 homolog B (PRPF40B).1 These mutations were mutually exclusive and their common functional consequence is believed to involve global abnormalities in RNA splicing, resulting in reduced cell proliferation and increased apoptosis.1

SF3B1 (located on chromosome 2q33.1) mutations in MDS-RS have also been reported by Papaemmanuil et al.2 and Visconte et al.3 At the time of this writing, details regarding the former study2 were not available, whereas in the latter study3 heterozygous SF3B1 mutations were reported in 9 (64%) of 14 patients with RARS, 13 (72%) of 18 patients with RARS and marked thrombocytosis (RARS-T), and none of 24 patients with MDS/MPN without RS.3 The most common SF3B1 mutation reported by Visconte et al.3 was SF3B1K700E (64%); other mutations described by these authors involved K666 (n=3), R625 (n=2), E622 (n=1), H662 (n=1) and del699-700QK (n=1). In the aforementioned study by Yoshida et al.,1 SF3B1 mutations also involved K700, K666, H662 and E622. Visconte et al.3 demonstrated that JAK2, MPL, LNK or DNMT3A mutations can co-occur with SF3B1 mutations and suggested an association between SF3B1 mutations and thrombosis.3 The objective of the current study was to define the prevalence of SF3B1 mutations in chronic-phase primary myelofibrosis (PMF) and investigate its prognostic relevance and phenotypic correlates. We were particularly interested in the presence or absence of bone marrow RS in SF3B1-mutated cases and whether or not the reported association with thrombosis can be confirmed.

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  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    T L Lasho, C M Finke, T Jimma, A Pardanani & A Tefferi

  2. Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

    C A Hanson

  3. Division of Cytogenetics, Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

    R A Knudson & R P Ketterling

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  1. T L Lasho
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Correspondence to A Tefferi.

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Lasho, T., Finke, C., Hanson, C. et al. SF3B1 mutations in primary myelofibrosis: clinical, histopathology and genetic correlates among 155 patients. Leukemia 26, 1135–1137 (2012). https://doi.org/10.1038/leu.2011.320

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