2. Academic Validation
  3. Altered RNA export by SF3B1 mutants confers sensitivity to nuclear export inhibition

Altered RNA export by SF3B1 mutants confers sensitivity to nuclear export inhibition

  • Leukemia. 2024 Jul 13. doi: 10.1038/s41375-024-02328-1.
Sana Chaudhry 1,  Felipe Beckedorff 1 2,  Shaista Shabbir Jasdanwala 3,  Tulasigeri M Totiger 1,  Maurizio Affer 1,  Abimbola Eunice Lawal 4,  Skye Montoya 1,  Francesco Tamiro 1,  Olivia Tonini 1,  Alexandra Chirino 1,  Andrew Adams 1,  Anya K Sondhi 1,  Stephen Noudali 1,  Alyssa Mauri Cornista 1,  Miah Nicholls 1,  Jumana Afaghani 1,  Paola Robayo 1,  Daniel Bilbao 1 5,  Stephen D Nimer 1 6,  Jose Antonio Rodríguez 7,  Shruti Bhatt 3,  Eric Wang 4,  Justin Taylor 8 9
Affiliations

Affiliations

  • 1 Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, FL, USA.
  • 2 Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 3 Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore, Singapore.
  • 4 The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • 5 Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 6 Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 7 Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
  • 8 Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, FL, USA. jxt1091@miami.edu.
  • 9 Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA. jxt1091@miami.edu.
PMID: 38997434 DOI: 10.1038/s41375-024-02328-1
Abstract

SF3B1 mutations frequently occur in Cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA Sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic pathways. To identify novel drug combinations that synergize with XPO1 inhibition, a forward genetic screen was performed with eltanexor treatment implicating anti-apoptotic targets BCL2 and BCLXL, which were validated by functional testing in vitro and in vivo. These targets were tested in vivo using SF3B1K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS.

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