Oncogenic SF3B1 mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability
Year: 2026
Type: article
Abstract: 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 messenger RNA (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 noncoding 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 a target gene, DCAF16, revealed multiple complex mutation-induced alterations in its 5' and 3' untranslated regions (UTRs). Remarkably, these were mechanistically associated with increased DCAF16 protein levels in SF3B1-mutant cells, representing, to our knowledge, the first time that oncogenic SF3B1 has been found 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 that coopt 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 UTRs and uncovers a novel strategy for the treatment of these important neoplasms.
Source: Blood
Authors: Michal Sekrecki, Agata Sekrecka, Rohan R. Lattupally, Kenny Le, Xiaokang Jin, Chen Mozes, Brendan G. Dwyer, Zhe Zhuang, Bryan A. Romero, Jose M. B. Pineda, Xunhong Cao, Linh Nguyen, Vicky Chen, Crystal M. Zhou, Jared A. Wallace, Kailee Tanaka, Charu Tiwari, Austin Gabel, Won Jun Kim, Robert F. Stanley, Salima Benbarche, Jaspreet Thind, Abhinaya Muruganandham, Tian Yi Zhang, Peter L. Greenberg, Jason R. Gotlib, Gabriel Mannis, William E. Shomali, Giselle Salmasi, Calvin Kuo, Tait Shanafelt, Irtisha Singh, Daichi Inoue, Finn K. Hansen, Nathanael S. Gray, Capucine van Rechem, Bita Fakhri, Xiaoyu Zhang, Sydney X. Lu
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
OpenAlex ID: W7125707141