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ResearchIn-Press PreviewHematologyOncology Open Access | 10.1172/JCI175619
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Liu, X. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Devadiga, S. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Stanley, R. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Morrow, R. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Janssen, K. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Quesnel-Vallières, M. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Pomp, O. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Moverley, A. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Li, C. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Skuli, N. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Carroll, M. in: JCI | PubMed | Google Scholar |
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Huang, J. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Wallace, D. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Lynch, K. in: JCI | PubMed | Google Scholar
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Abdel-Wahab, O. in: JCI | PubMed | Google Scholar |
1Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, United States of America
2Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States of America
3Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States of America
5Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, United States of America
6Coriell Institute for Medical Research, Coriell Institute for Medical Research, Camden, United States of America
7Department of Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, New York, United States of America
8Division of Hematology-Oncology, Univeristy of Pennsylvania, Philadelphia, United States of America
Find articles by Klein, P. in: JCI | PubMed | Google Scholar
Published May 7, 2024 - More info
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 SRSF2P95H/+ 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. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ 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 SRSF2P95H mutant MDS and AML.