Oncogenic SF3B1 mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability.

Oncogenic mutations of SF3B1 are common in myeloid cancers, chronic lymphocytic leukemia (CLL) and select solid tumors. Their mechanistic basis for promoting oncogenesis has been investigated in detail, with the stereotyped missplicing of mRNA protein coding sequences most intensively studied. These changes, in genes such as MAP3K7, BRD9, and ABCB7, typically lead to loss-of-function, thus contributing to cancer pathogenesis.Here we systematically analyzed the impact of mutant SF3B1 on non-coding regions of mRNA transcripts across disease types, in both cell lines and primary patient specimens. This identified numerous novel and highly reproducible splicing alterations in such regions. Studies of one target gene, DCAF16, revealed multiple complex mutation-induced alterations in its 5' and 3' untranslated regions (5', 3' UTRs). Remarkably, these were mechanistically associated with increased DCAF16 protein levels in SF3B1 mutant cells, representing the first time that oncogenic SF3B1 has been shown to increase levels of a target protein in a gain-of-function manner. DCAF16 is a substrate recognition adapter for the DDB1/CUL4 E3 ubiquitin ligase complex. Novel protein degrader small molecules which co-opt DCAF16 to degrade BRD4 as a neosubstrate demonstrated preferential selectivity for SF3B1 mutant cancers and CLL primary patient specimens due to increased DCAF16 protein levels. In turn, this reveals the therapeutic relevance of mutant SF3B1 dysregulation of transcript untranslated regions and uncovers a novel strategy for the treatment of these important neoplasms.

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Journal
Blood
Published
2026-01-26
DOI
https://doi.org/10.1182/blood.2025029972
Primary Topic
Protein Degradation and Inhibitors
Type
article
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article

Oncogenic SF3B1 mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability.

Chen Mozes, Austin M. Gabel, J. Gotlib, Crystal Zhou et al.
Blood
Protein Degradation and Inhibitors
article

Oncogenic SF3B1 mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability.

Chen Mozes, Austin M. Gabel, J. Gotlib, Crystal Zhou, Charu Tiwari, Brendan G. Dwyer, K. Tanaka, Belén Romero, Zhe Zhuang, Sydney X. Lu, Jaspreet Thind, Finn K. Hansen, Salima Benbarche, Jose Mario Bello Pineda, Agata Sekrecka, Kenny Le, William E. Shomali, Bita Fakhri, Jared Wallace, Capucine Van Rechem, Tait Shanafelt, Gabriel N. Mannis, Vicky Chen, C. L. Kuo, Rohan Lattupally, Irtisha Singh, Xiaokang Jin, Tian Yi Yi Zhang, Won Jun Kim, Xunhong Cao, Peter L. Greenberg, Nathanael S Gray, Michal Sekrecki, Linh Nguyen, Abhinaya Muruganandham, Robert F. Stanley, Giselle Ghazal Salmasi, Xiaoyu Zhang, Daichi Inoue
article en

Abstract

Oncogenic mutations of SF3B1 are common in myeloid cancers, chronic lymphocytic leukemia (CLL) and select solid tumors. Their mechanistic basis for promoting oncogenesis has been investigated in detail, with the stereotyped missplicing of mRNA protein coding sequences most intensively studied. These changes, in genes such as MAP3K7, BRD9, and ABCB7, typically lead to loss-of-function, thus contributing to cancer pathogenesis.Here we systematically analyzed the impact of mutant SF3B1 on non-coding regions of mRNA transcripts across disease types, in both cell lines and primary patient specimens. This identified numerous novel and highly reproducible splicing alterations in such regions. Studies of one target gene, DCAF16, revealed multiple complex mutation-induced alterations in its 5' and 3' untranslated regions (5', 3' UTRs). Remarkably, these were mechanistically associated with increased DCAF16 protein levels in SF3B1 mutant cells, representing the first time that oncogenic SF3B1 has been shown to increase levels of a target protein in a gain-of-function manner. DCAF16 is a substrate recognition adapter for the DDB1/CUL4 E3 ubiquitin ligase complex. Novel protein degrader small molecules which co-opt DCAF16 to degrade BRD4 as a neosubstrate demonstrated preferential selectivity for SF3B1 mutant cancers and CLL primary patient specimens due to increased DCAF16 protein levels. In turn, this reveals the therapeutic relevance of mutant SF3B1 dysregulation of transcript untranslated regions and uncovers a novel strategy for the treatment of these important neoplasms.

Blood
Northwestern University (US), Osaka Gakuin University (JP), SRI International (US), Cancer Prevention Institute of California (US), Memorial Sloan Kettering Cancer Center (US), University of Bonn (DE), Palo Alto University (US), University of Washington (US), Medical College of Wisconsin (US), Northwestern University (PH), Texas A&M Health Science Center (US), Stanford Medicine (US), Stanford Cancer Institute, Stanford University (US), The University of Osaka (JP)
Good health and well-being
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Protein Degradation and Inhibitors
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