SomaticSF3B1Mutation in Myelodysplasia with Ring Sideroblasts

Abstract

Background Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. Methods We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. Results We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. Conclusions Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.)

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

“…Thus far, in CMML loss of function gene mutations involving ASXL1 and EZH2 have been associated with poor outcome [10,11]. Recently, mutations involving the spliceosome machinery have been described in patients with myeloid neoplasms, including MDS, CMML, MPN, and AML [12,13,17,18,30]. Spliceosome aberrations have also been described in solid tumors, examples being recurrent somatic mutations of U2AF35 in adenocarcinoma of the lung [31], and overexpression of SRSF1 and SRSF2 in both adeno and squamous cell lung cancers [32].…”

“…Mutations involving SF3B1 are common in MDS-RS ( 80%), and to a lesser extent in PMF (<10%), but hold no independent prognostic value [12,17,25]. These mutations have a strong phenotypic correlation with the presence of BM RS.…”

“…Similarly, these mutations are seen in a small fraction (<10%) of patients with primary myelofibrosis (PMF), are strongly associated with the presence of BM RS, but do not affect disease outcome [17]. SRSF2 mutations are seen in patients with MDS, CMML, MPN/PMF, and acute myeloid leukemia (AML) [12,13,16,[18][19][20], and are very rare in juvenile myelomonocytic leukemia [19,21]. In MDS and PMF, SRSF2 mutations are relatively common ( 15-20%) and are associated with shortened OS and LFS [16,18,22].…”

“…Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11]. The data with regard to the other mutations needs further elucidation.Mutations in genes of the splicing machinery, such as SF3B1 (splicing factor 3B, subunit 1), SRSF2 (serine/arginine-rich splicing factor 2) and U2AF35, also known as U2AF1 (U2 small nuclear RNA auxiliary factor) are common in patients with myeloid malignancies [12][13][14]. SF3B1 mutations have a high prevalence ( 80%) in MDS and ring sideroblasts (RS) and do not influence either OS or leukemiafree survival (LFS) [15,16].…”

“…Similarly, these mutations are seen in a small fraction (<10%) of patients with primary myelofibrosis (PMF), are strongly associated with the presence of BM RS, but do not affect disease outcome [17]. SRSF2 mutations are seen in patients with MDS, CMML, MPN/PMF, and acute myeloid leukemia (AML) [12,13,16,[18][19][20], and …”