Integrative RNA-omics Discovers GNAS Alternative Splicing as a Phenotypic Driver of Splicing Factor-Mutant Neoplasms

Area of Science:

• Hematology
• Molecular Biology
• Oncology

Background:

• Splicing factor (SF) mutations are common in myelodysplastic syndrome (MDS).
• Downstream drivers of MDS caused by SF mutations are not fully understood.

Purpose of the Study:

• Identify common direct targets of missplicing by mutant U2AF1 and SRSF2.
• Elucidate the role of these targets in MDS pathogenesis and therapeutic potential.

Main Methods:

• RNA sequencing and cross-linking immunoprecipitation (CLIP) in human hematopoietic stem/progenitor cells.
• Isogenic induced pluripotent stem cell (iPSC) models.
• Integrative analyses of alternative splicing and protein binding.

Main Results:

• Convergent missplicing by mutant U2AF1 and SRSF2 promotes a long GNAS isoform (GNAS-L).
• GNAS-L encodes a hyperactive Gαs-L subunit, activating ERK/MAPK signaling.
• SF-mutant MDS cells exhibit activated ERK signaling and sensitivity to MEK inhibitors.

Conclusions:

• GNAS-L is a unifying driver of SF-mutant MDS.
• Targeting ERK/MAPK signaling offers a therapeutic strategy for MDS.
• Findings reveal a common oncogenic mechanism for SRSF2 and U2AF1 mutations.