Vicky Chen

All Publications

• Oncogenic SF3B1 mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability. Blood Sekrecki, M., Sekrecka, A., Lattupally, R. R., Le, K., Jin, X., Mozes, C., Dwyer, B. G., Zhuang, Z., Romero, B. A., Pineda, J. M., Cao, X., Nguyen, L., Chen, V. W., Zhou, C., Wallace, J. A., Tanaka, K. L., Tiwari, C., Gabel, A., Kim, W. J., Stanley, R. F., Benbarche, S., Thind, J., Muruganandham, A., Zhang, T. Y., Greenberg, P. L., Gotlib, J., Mannis, G. N., Shomali, W., Salmasi, G. G., Kuo, C. J., Shanafelt, T. D., Singh, I., Inoue, D., Hansen, F. K., Gray, N. S., Van Rechem, C., Fakhri, B., Zhang, X., Lu, S. X. 2026

  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.

  View details for DOI 10.1182/blood.2025029972

  View details for PubMedID 41587094

• Novel therapeutics for SF3B1 mutant cancers which exploit the missplicing of DCAF16 Sekrecki, M., Sekrecka, A., Lattupally, R., Le, K., Cao, X., Chen, V., Zhuang, Z., Dwyer, B., Zhou, C., Tiwari, C., Gabel, A., Kim, W., Stanley, R., Benbarche, S., Pineda, J., Gray, N., Zhang, T., Greenberg, P., Gotlib, J., Mannis, G., Shomali, W., Salmasi, G., Shanafelt, T., Van Rechem, C., Zhang, X., Fakhri, B., Lu, S. ELSEVIER. 2025: 1474-1475

  View details for DOI 10.1182/blood-2025-1474

  View details for Web of Science ID 001658978100025

• Integrative analysis of mRNA stability regulation uncovers a metastasis-suppressive program in breast cancer. bioRxiv : the preprint server for biology Karner, H., Mittmann, T., Chen, V. W., Borah, A. A., Langen, A., Yousefi, H., Fish, L., Zaro, B. W., Navickas, A., Goodarzi, H. 2025

  Abstract

  Heterogeneity in cancer gene expression is typically linked to genetic and epigenetic alterations, yet post-transcriptional regulation likely influences these patterns as well. However, the quantitative contribution of post-transcriptional mechanisms to cancer transcriptome dynamics remains unclear. Here, we systematically measured mRNA dynamics across diverse breast cancer models, revealing that mRNA stability significantly shapes gene expression variability. To decipher the regulatory grammar underlying these dynamics, we developed GreyHound, an interpretable multimodal deep-learning framework integrating RNA sequence features and RNA-binding protein (RBP) expression. GreyHound identified an extensive network of RBPs and their regulons underlying variations in mRNA stability. Among these, we uncovered a metastasis-suppressive regulatory axis centered on the RNA-binding protein RBMS3 and its post-transcriptional control of the redox regulator TXNIP. Functional and molecular analyses revealed that RBMS3 depletion resulted in targeted transcript destabilization, which was associated with poor clinical outcomes and enhanced metastatic potential in xenograft models. Using in vivo epistasis studies, we confirmed that RBMS3 regulation of TXNIP mRNA stability drives this metastasis-suppressive program. These findings position the RBMS3-TXNIP regulatory axis as a key post-transcriptional mechanism in breast cancer and illustrate how interpretable models of RNA dynamics can uncover hidden regulatory programs in disease.

  View details for DOI 10.1101/2025.06.06.658309

  View details for PubMedID 40501975