A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies
Xiaolei Liu, … , Omar Abdel-Wahab, Peter S. Klein
Xiaolei Liu, … , Omar Abdel-Wahab, Peter S. Klein
Published May 7, 2024
Citation Information: J Clin Invest. 2024;134(12):e175619. https://doi.org/10.1172/JCI175619.
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A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies

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 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.

Authors

Xiaolei Liu, Sudhish A. Devadiga, Robert F. Stanley, Ryan M. Morrow, Kevin A. Janssen, Mathieu Quesnel-Vallières, Oz Pomp, Adam A. Moverley, Chenchen Li, Nicolas Skuli, Martin Carroll, Jian Huang, Douglas C. Wallace, Kristen W. Lynch, Omar Abdel-Wahab, Peter S. Klein

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Figure 2

Selective cytotoxicity of GSK-3i in primary human leukemia cells with splicing factor mutations.

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Selective cytotoxicity of GSK-3i in primary human leukemia cells with sp...
(A) CHIR induced higher levels of apoptosis in splicing factor mutant (MUT) cells from patients with CMML (purple) or AML (red) compared with patients with WT splicing factors or CD34+ cells from healthy donors (black). The log2[fold change] in apoptosis in CHIR-treated relative to DMSO-treated cells is shown. Genetic information for each patient is shown in Supplemental Table 1. Statistical analysis was performed using a 2-tailed Mann-Whitney test. (B) Schematic of lentivirus infection in primary AML cells for apoptosis assay. (C) Primary AML cells from 3 patients were transduced with lentivirus encoding WT or mutant SRSF2 as in B and cultured in the absence or presence of 3 μM CHIR (blue boxes indicate duration of drug treatment). The percentage of mCherry-positive cells normalized to the number at day 3 (patients 1 and 2) or day 4 (patient 3) is shown. (D) Representative flow cytometric analysis (left) and quantification (right) of apoptosis in primary cells from patients with AML overexpressing either SRSF2+ or SRSF2P95H, as measured by annexin V and 7-AAD staining in the absence or presence of 3 μM CHIR. Data in C and D are presented as the mean ± SD; **P < 0.01 and ****P < 0.0001 (2-way ANOVA with Šidák’s multiple-comparison test).