Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms

Abstract

Precursor mRNA splicing is catalyzed by the spliceosome, a macromolecule composed of small nuclear RNAs associated with proteins. The SF3B1 gene encodes subunit 1 of the splicing factor 3b, which is important for anchoring the spliceosome to precursor mRNA. In 2011, wholeexome sequencing studies showed recurrent somatic mutations of SF3B1 and other genes of the RNA splicing machinery in patients with myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm. SF3B1 mutations had a particularly high frequency among conditions characterized by ring sideroblasts, which is consistent with a causal relationship. SF3B1 mutants were also detected at a lower frequency in a variety of other tumor types. In chronic lymphocytic leukemia, SF3B1 was found to be the second most frequently mutated gene. In myelodysplastic syndromes, SF3B1 mutations appear to be founding genetic lesions and are associated with a low risk of leukemic evolution. In contrast, SF3B1 mutations have a lower incidence in early stages of chronic lymphocytic leukemia, are more common in advanced disease, and tend to be associated with poor prognosis, suggesting that they occur during clonal evolution of the disease. The assessment of SF3B1 mutation status may become innovative diagnostic and prognostic tools and the availability of spliceosome modulators opens novel therapeutic prospects. (Blood. 2013; 121(2):260-269)

Targeted re-sequencing analysis of 25 genes commonly mutated in myeloid disorders in del(5q) myelodysplastic syndromes

“…15,43,47 It has been suggested that multipotent hematopoietic stem cells initially attain a splicing factor mutation as a founding genetic lesion, and subsequently acquire additional mutations that drive their malignant transformation. 43,48 This is consistent with our finding in one 5q-syndrome case with a high SF3B1 mutant allele frequency and two other mutations (ASXL1 and TET2) with lower mutant allele frequencies.…”

Myeloid neoplasms with germline DDX41 mutation

“…Similarly, mutations in PRPF8 have been identified in MDS and AML patients where decreased PRPF8 expression is associated with increased exon skipping [53], possibly due to a splicing proofreading defect [53]. While DDX41 R525H is associated with reduced binding to SF3B1 and PRPF8, DDX41 mutations have not been reported in association with MDS with ring sideroblasts that is often characteristic of mutations in SF3B1 [50] and PRPF8 [53].…”

“…Somatic mutations in SF3B1 are frequently found in MDS and chronic lymphocytic leukemia (CLL) patients [50,51]. Studies suggest that mutations in SF3B1 induce malignancy through aberrant transcription, altered pre-mRNA recognition and alternative splicing [50,52]. Similarly, mutations in PRPF8 have been identified in MDS and AML patients where decreased PRPF8 expression is associated with increased exon skipping [53], possibly due to a splicing proofreading defect [53].…”

“…Mutations in SF3B1 and PRPF8 have been seen in numerous studies of myeloid malignancies, particularly MDS [48,49]. Somatic mutations in SF3B1 are frequently found in MDS and chronic lymphocytic leukemia (CLL) patients [50,51]. Studies suggest that mutations in SF3B1 induce malignancy through aberrant transcription, altered pre-mRNA recognition and alternative splicing [50,52].…”

Novel prognostic molecular factors: a quantum leap in the field of chronic lymphocytic leukemia

“…SF3B1 is the core protein of snRNP in classical spliceosome. Its role is to recognize the branch side of premRNA, and, subsequently, to bind it with the spliceosome, what is the initial stadium of splicing [57,58]. The abnormalities of this regulation, which are associated with the mutations in SF3B1 gene, may lead to unintended introns retention, and, consequently, to forming alternative, modified transcripts [59].…”