1. Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition.
- Author
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Potts KS, Cameron RC, Metidji A, Ghazale N, Wallace L, Leal-Cervantes AI, Palumbo R, Barajas JM, Gupta V, Aluri S, Pradhan K, Myers JA, McKinstry M, Bai X, Choudhary GS, Shastri A, Verma A, Obeng EA, and Bowman TV
- Subjects
- Mice, Humans, Animals, RNA Splicing Factors genetics, RNA Splicing Factors metabolism, RNA Splicing genetics, Hematopoietic Stem Cells metabolism, Mutation genetics, Phosphoproteins metabolism, STAT3 Transcription Factor genetics, Zebrafish metabolism, Hematopoiesis genetics
- Abstract
Hematopoietic stem and progenitor cells (HSPCs) sustain lifelong hematopoiesis. Mutations of pre-mRNA splicing machinery, especially splicing factor 3b, subunit 1 (SF3B1), are early lesions found in malignancies arising from HSPC dysfunction. However, why splicing factor deficits contribute to HSPC defects remains incompletely understood. Using zebrafish, we show that HSPC formation in sf3b1 homozygous mutants is dependent on STAT3 activation. Clinically, mutations in SF3B1 are heterozygous; thus, we explored if targeting STAT3 could be a vulnerability in these cells. We show that SF3B1 heterozygosity confers heightened sensitivity to STAT3 inhibition in zebrafish, mouse, and human HSPCs. Cells carrying mutations in other splicing factors or treated with splicing modulators are also more sensitive to STAT3 inhibition. Mechanistically, we illustrate that STAT3 inhibition exacerbates aberrant splicing in SF3B1 mutant cells. Our findings reveal a conserved vulnerability of splicing factor mutant HSPCs that could allow for their selective targeting in hematologic malignancies., Competing Interests: Declaration of interests A.V. participates on the advisory boards for Stelexis, Bakx, Novartis, Acceleron, and Celgene, which includes stock options, received a consultation fee from Janssen Pharmaceuticals, and received research funding from Prelude, BMS, GSK, Incyte, Medpacto, Curis, and Eli Lilly. A.S. has received an honorarium from GLG, Guidepoint, Onclive, a consultation fee from Janssen Pharmaceuticals, an advisory board fee from Rigel Pharmaceuticals, and research funding from Kymera Therapeutics., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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