SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition

Abstract

SUMMARY Mutations affecting spliceosomal proteins are the most common class of mutations in patients with myelodysplastic syndromes (MDS), yet their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2’s normal sequence-specific RNA binding activity, thereby altering recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2 that triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in splicing of key regulators, and impaired hematopoiesis.

Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia

“…Recent findings suggest that IDH2 and SRSF2 mutations cooperate to induce a lethal transplantable myeloproliferative neoplasm 5. Additionally, SRSF2 mutation is known to induce alternative splicing of genes involved in the apoptotic pathway, a possible link to venetoclax sensitivity 6. We note that FLT3‐ITD or PTPN11 mutations may confer primary and secondary resistance to venetoclax.…”

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

“…To confirm that somatic gene mutations prime HSPCs for pyroptosis in MDSs, we performed comparative analyses of published gene expression profiles from human and murine SRSF2 (GSE65349) and U2AF1 mutants (GSE30195 and GSE66793) vs WT, TET2 knockout (GSE27816), and primary MDS (GSE19429) vs normal HSPCs and found uniform upregulation of pyroptosis effectors, consistent with transcriptional priming. [39][40][41][42][43] Importantly, in MDS BM specimens, BM plasma concentration of S100A9 positively correlated with NLRP3 MFI, percentage and MFI of plasma ASC specks, and the presence of SGMs and variant allele frequency (supplemental Figure 8). Furthermore, both the percentage and MFI of plasma ASC specks were significantly increased in MDS patients harboring SGMs (supplemental Figure 8D-E).…”

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

“…Mutations in components of the spliceosome (including SRSF2, U2AF1 and SF3B1) are strongly correlated with an MF (or MPN/MDS overlap) phenotype, as are mutations in ASXL1 and EZH2, which are prevalent in MDS and de novo AML and associated with leukemic transformation and a worse overall survival in MPNs. 39,62,75,121 This may be related to the deregulation of PRC2 and derepression of stem cell signature genes, causing increased stem cell self renewal, as discussed above 77,79,81 ( Figure 3). Finally, mutations in NRAS and CBL are also more frequently seen in patients with MF, atypical chronic myeloid leukemia and chronic myelomonocytic leukemia, and are associated with poorer overall survival.…”

“…SRSF2 mutations appear to result specifically in skewed mRNA motif recognition (rather than loss of function), which is associated with alterations in exon usage in a number of genes. These include EZH2 (leading to reduced expression), and bcl-6 corepressor (BCOR), 81 which is also known to be mutated in myeloid malignancies. U2AF1 mutations alter its 3' splice acceptor preferences leading to mis-splicing of a set of genes that includes BCOR and SRSF2.…”