Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations

Abstract

Splicing factors are frequently mutated in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations are presumed to contribute to oncogenic transformation, but the underlying mechanisms remain incompletely understood. While no specific treatment option is available for MDS/AML patients with spliceosome mutations, novel targeting strategies are actively explored, leading to clinical trials of small molecule inhibitors that target the spliceosome, DNA damage response pathway, and immune response pathway. Here, we review recent progress in mechanistic understanding of splicing factor mutations promoting disease progression and summarize potential therapeutic strategies, which, if successful, would provide clinical benefit to patients carrying splicing factor mutations.

Keywords: DNA damage response; acute myeloid leukemia; immune response pathway; myelodysplastic syndromes; spliceosome.

Figure 1

Approaches to targeting splicing factor mutations in splicing factor-mutant myelodysplastic syndromes/acute myeloid leukemia. Cells harboring splicing factor mutations have increased R loops and dysregulation of innate immune and inflammatory pathways. The elevated R-loop formation results in activation of the ATR signaling pathway and DNA-damage response. Leukemic cells harboring splicing factor mutations preferentially respond to ATR/CHK1/WEE1 inhibition and immune targeting agents (Inflammasome, Cytokines). In addition, cells with splicing factor mutations are more sensitive to splicing modulators that selectively inhibit SF3B1, RBM39, and arginine methyltransferase (PRMT) activity.