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• W4382073199 abstract "Summary Myelodysplastic syndrome (MDS) is a clonal disorder characterized by hyperproliferation and dysplasia of hematopoietic progenitor cells, deficiencies in circulating blood cells, and progression to acute myeloid leukemia (AML). Splicing factor mutations are common in MDS, but how they alter cellular functions remains unclear. We show that increased mitophagy is a common feature in SRSF2 P95* mutated MDS and AML. The SRSF2 P95H/+ mutation alters the splicing of multiple mRNAs encoding mitochondrial proteins, impairs mitochondrial function, and increases mitophagy compared to isogenic cells with wild-type SRSF2 . We also identify a mechanism of mitochondrial surveillance mediated by PINK1 ( PTEN Induced Kinase 1 ). PINK1 mRNA is alternatively spliced to a form that retains an intron with a premature termination codon, yielding an unstable mRNA and reduced PINK1 mRNA abundance. Mitochondrial stress promotes excision of this poison intron, stabilizing the mRNA and increasing PINK1 mRNA and protein. Similarly, SRSF2 P95H induces mitochondrial defects and increases PINK1 expression by promoting removal of the poison intron. In contrast, disrupting splicing by inhibiting glycogen synthase kinase 3 promotes retention of the poison intron, reducing PINK1 mRNA, impairing mitophagy, and activating apoptosis in SRSF2 P95H/+ cells. These data reveal a mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as both a hallmark and a therapeutic vulnerability in SRSF2 P95H mutant MDS and AML." @default.
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• W4382073199 date "2023-06-25" @default.
• W4382073199 modified "2023-09-26" @default.
• W4382073199 title "Targeting mitophagy in<i>SRSF2</i>mutant hematologic malignancies" @default.
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• W4382073199 doi "https://doi.org/10.1101/2023.06.25.546449" @default.
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