Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition

Kathryn S. Potts, Rosannah C. Cameron, Amina Metidji, Noura Ghazale, La Shanale Wallace, Ana I. Leal-Cervantes, Reid Palumbo, Juan Martin Barajas, Varun Gupta, Srinivas Aluri, Kith Pradhan, Jacquelyn A. Myers, Mia McKinstry, Xiaoying Bai, Gaurav S. Choudhary, Aditi Shastri, Amit K. Verma, Esther A. Obeng, Teresa V. Bowman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number111825
JournalCell Reports
Volume41
Issue number11
DOIs
StatePublished - Dec 13 2022

Keywords

  • CP: Molecular biology
  • CP: Stem cell research
  • hematopoietic stem and progenitor cell
  • myelodysplastic syndrome
  • SF3B1
  • splicing factor
  • STAT3
  • zebrafish

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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