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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.
Pubmed ID: 38997434
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Mus musculus with name C57BL/6J from IMSR.
View all literature mentionsCell line NALM-6 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line MOLM-13 is a Cancer cell line with a species of origin Homo sapiens (Human)
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Mus musculus with name B6.SJL-Ptprca Pepc
Cell line K-562 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line U-937 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsProvides researchers with sophisticated methods for analysis and preparative sorting of both normal and tumor cells. Helps researchers to measure parameters including apoptosis, gene expression, drug metabolism, immune responses and pathways of cellular activation, both normal and tumor related. Provides access to high parameter cytometry instrumentation including spectral cytometry, mass cytometry and imaging mass cytometry.
View all literature mentionsProvides small animal cancer modeling services to foster cancer research and to accelerate discovery of tailored anti-tumor therapies, including preclinical data for drug development, proof of principle for novel therapies, preclinical imaging, and disease biomarker studies. Services include facilitating in vivo modeling of human disease using mouse models; supporting preclinical in vivo efficacy and toxicity studies; devising treatment protocols; using noninvasive imaging for diagnosis and evaluation of responses to treatment; and performing histopathological analysis of targeted cancer therapies. Specific services include (1) support for the development of experimental murine models of cancer, including with cell line and patient-derived xenografts (PDXs), genetically engineered mouse models, and humanized models; (2) support for devising and implementing treatment protocols in a pre-clinical setting using murine models of human disease (e.g., drug toxicology and efficacy studies, drug formulation and delivery, and related assessments, like cell blood count, clinical chemistry, and flow cytometry analysis); and (3) diagnosis and evaluation of responses to treatment, using noninvasive small animal imaging for diagnosis and evaluation of responses to treatment, including in vivo bioluminescence and fluorescence optical imaging, high-frequency ultrasound imaging, structural and functional nuclear imaging, and magnetic resonance imaging (MRI); and (b) research histopathological analysis of targeted cancer therapies, including H&E and immunohistochemistry (IHC) sectioning, staining, scanning and analysis, and data storage of digital slide images. The CMSR also offers consultation, training, educational workshops and seminars. CMSR radiotherapy services support both small animal total body and image-guided radiation treatment delivery with sub-millimetric accuracy for development of radiation therapy regimens in a preclinical setting.
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