1. A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies
- Author
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Liu, Xiaolei, Devadiga, Sudhish A., Stanley, Robert F., Morrow, Ryan M., Janssen, Kevin A., Quesnel-Vallieres, Mathieu, Pomp, Oz, Moverley, Adam A., Li, Chenchen, Skuli, Nicolas, Carroll, Martin, Huang, Jian, Wallace, Douglas C., Lynch, Kristen W., Abdel-Wahab, Omar, and Klein, Peter S.
- Subjects
Oncology, Experimental ,Gene mutations -- Research ,Gene expression -- Research ,Myelodysplastic syndromes -- Development and progression -- Genetic aspects ,Mitochondria -- Genetic aspects -- Health aspects ,Cancer -- Research ,Health care industry - Abstract
Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic [SRSF2.sup.P95H/+] mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. [SRSF2.sup.P95H]-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of [SRSF2.sup.P95H/+] cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in [SRSF2.sup.P95H/+] cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in [SRSF2.sup.P95H] mutant MDS and AML., Introduction Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by hyperproliferative bone marrow, dysplastic hematopoietic cells, peripheral cytopenias, and high risk of progression to acute myeloid leukemia (AML). Recurrent [...]
- Published
- 2024
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