Impact of Splicing Factor Mutations on Pre-mRNA Splicing in the Myelodysplastic Syndromes

Abstract

Splicing is an essential cellular process which is carried out by the spliceosome in order to remove the introns and join the exons present in pre-mRNA transcripts. A variety of spliceosomal mutations have been recently identified in the myelodysplastic syndromes (MDS), a heterogeneous group of hematopoietic stem cell malignancies, revealing a new leukemogenic pathway involving spliceosomal dysfunction. Splicing factor genes are the most frequently mutated genes found in MDS, with mutations occurring in more than half of all patients. The high mutation frequency in different components of the spliceosome in MDS indicates that aberrant splicing may be a common consequence of these mutations in this disorder. RNA sequencing studies using MDS patient bone marrow cells and different mouse models have identified several downstream targets of the splicing factor mutations. Aberrant splicing of these target genes may contribute to MDS pathogenesis, however functional studies are required in order to fully determine the effects of the aberrant isoforms on disease phenotype. Splicing inhibitors are currently being developed and may be used as therapeutic agents to target aberrant pre-mRNA splicing in MDS and other cancers with splicing factor mutations. The mouse models expressing splicing factor mutations may prove particularly valuable for pre-clinical testing of these drugs.

SF3B1 mutations induce R-loop accumulation and DNA damage in MDS and leukemia cells with therapeutic implications

“…Preferential sensitivity of splicing factor mutant cells towards splicing modulators has been reported previously [ 4 , 14 , 15 ]. Thus, we investigated whether a splicing modulator could increase the sensitivity of SF3B1 mutant cells to ATR or Chk1 inhibition.…”

“…The myelodysplastic syndromes (MDS) are common myeloid malignancies characterized by ineffective hematopoiesis and blood cytopenias, with patients showing increasing bone marrow blasts with disease progression [ 1 ]. Mutations in genes involved in pre-mRNA splicing ( SF3B1, SRSF2, U2AF1, and ZRSR2 ) are the most common mutations found in MDS, occurring in over 50% of all cases [ 2 – 4 ]. There is evidence that some spliceosome components play a role in the maintenance of genomic stability [ 5 ].…”

“…SF3B1 is the most frequently mutated splicing factor gene in MDS, with mutations occurring in 25–30% of MDS patients [ 9 – 11 ]. SF3B1 mutations are also found at lower frequency in other hematological malignancies [ 4 , 11 ] and in some individuals with clonal hematopoiesis of indeterminate potential [ 12 ]. A role of SF3B1 mutations in R-loop accumulation and DNA damage has not yet been reported in hematopoietic cells.…”

From General Aberrant Alternative Splicing in Cancers and Its Therapeutic Application to the Discovery of an Oncogenic DMTF1 Isoform

“…Especially, they regulate exon inclusion through binding to the ESEs and ISE [16]. Meanwhile, SR proteins are involved in other biological processes, including transcription, mRNA nuclear export, translation, and nonsense-mediated decay (NMD) [17,18,19]. hnRNPs may cause exon skipping through their association with ESSs and ISSs.…”

Flow cytometric analysis identifies changes in S and M phases as novel cell cycle alterations induced by the splicing inhibitor isoginkgetin

“…There are many small molecule inhibitors of pre-mRNA splicing and many, if not all of them, appear to exhibit anti-neoplastic activity in many cancer cell types [ 5 – 9 ]. Cell cycle analysis based on DNA content indicates that inhibition of pre-mRNA splicing leads to the accumulation of cells with G 1 and G 2 /M DNA content and a decrease in the proportion of cells in S phase [ 10 – 12 ].…”