Browsing by Author "Zhao, Bin"

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    Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity
    (Elsevier, 2019-03-12) Aho, Erin R.; Wang, Jing; Gogliotti, Rocco D.; Howard, Gregory C.; Phan, Jason; Acharya, Pankaj; Macdonald, Jonathan D.; Cheng, Ken; Lorey, Shelly L.; Lu, Bin; Wenzel, Sabine; Foshage, Audra M.; Alvarado, Joseph; Wang, Feng; Shaw, J. Grace; Zhao, Bin; Weissmiller, April M.; Thomas, Lance R.; Vakoc, Christopher R.; Hall, Matthew D.; Hiebert, Scott W.; Liu, Qi; Stauffer, Shaun R.; Fesik, Stephen W.; Tansey, William P.; Biochemistry and Molecular Biology, School of Medicine
    The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.
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    Ldb1 is required for Lmo2 oncogene–induced thymocyte self-renewal and T-cell acute lymphoblastic leukemia
    (American Society of Hematology, 2020-06-18) Li, LiQi; Mitra, Apratim; Cui, Kairong; Zhao, Bin; Choi, Seeyoung; Lee, Jan Y.; Stamos, Daniel B.; El-Khoury, Dalal; Warzecha, Claude; Pfeifer, Karl; Hardwick, Joyce; Zhao, Keji; Venters, Bryan; Davé, Utpal P.; Love, Paul E.; Medicine, School of Medicine
    Prolonged or enhanced expression of the proto-oncogene Lmo2 is associated with a severe form of T-cell acute lymphoblastic leukemia (T-ALL), designated early T-cell precursor ALL, which is characterized by the aberrant self-renewal and subsequent oncogenic transformation of immature thymocytes. It has been suggested that Lmo2 exerts these effects by functioning as component of a multi-subunit transcription complex that includes the ubiquitous adapter Ldb1 along with b-HLH and/or GATA family transcription factors; however, direct experimental evidence for this mechanism is lacking. In this study, we investigated the importance of Ldb1 for Lmo2-induced T-ALL by conditional deletion of Ldb1 in thymocytes in an Lmo2 transgenic mouse model of T-ALL. Our results identify a critical requirement for Ldb1 in Lmo2-induced thymocyte self-renewal and thymocyte radiation resistance and for the transition of preleukemic thymocytes to overt T-ALL. Moreover, Ldb1 was also required for acquisition of the aberrant preleukemic ETP gene expression signature in immature Lmo2 transgenic thymocytes. Co-binding of Ldb1 and Lmo2 was detected at the promoters of key upregulated T-ALL driver genes (Hhex, Lyl1, and Nfe2) in preleukemic Lmo2 transgenic thymocytes, and binding of both Ldb1 and Lmo2 at these sites was reduced following Cre-mediated deletion of Ldb1. Together, these results identify a key role for Ldb1, a nonproto-oncogene, in T-ALL and support a model in which Lmo2-induced T-ALL results from failure to downregulate Ldb1/Lmo2-nucleated transcription complexes which normally function to enforce self-renewal in bone marrow hematopoietic progenitors.