Feb. 13 Seminar: Jason X. Cheng, MD, PhD – Novel Chromatin Structure-based Therapeutics in MDS and AML
Monday, February 13, 4:00 pm – 5:00 pm, Pancoe Auditorium
Jason X. Cheng, MD, PhD, University of Chicago
Title: Novel Chromatin Structure-based Therapeutics in MDS and AML: Targeting RNA/hnRNPK-mediated Chromatin Structure and BRD4/BET-mediated Drug Resistance
Abstract: Disease-associated chromatin structure and its role in the regulation of drug response and resistance are poorly understood. Here we demonstrate that RNA/hnRNPK mediates lineage-specific chromatin organization and differential response to 5-azacytidine (5-AZA), and aberrant phosphorylation of the CTD of RNA polymerase II by BRD4/2 controls 5-AZA resistance in myeloid leukemia cells. Our data show that cell lineage-determining transcription factors (GATA1 and SPI1/PU.1) selectively interact with different sets of chromatin modifiers in erythroid vs. monocytic leukemia cells, and such interactions are mediated by RNA/hnRNPK. HnRNPK also binds m5C-RNA methyltransferases (m5C-RMTs) and methylated RNA as well as CDK9/P-TEFb to recruit active RNA-polymerase-II (RNA-pol-II) and form active chromatin structure at nascent RNA sites. 5-azacytidine causes rapid disassociation of hnRNPK from the transcription factors from RNA-pol-II and disruption of the RNA/hnRNPK/m5C-RMTs-mediated active chromatin structure. We further demonstrate a significant increase in BRD4/2 and a massive BRD4/2-mediated phosphorylation of the CTD of RNA polymerase II, which leads to formation of aberrantly active chromatin structure on nascent RNA in 5-AZA-resistant leukemia cells, compared to 5-AZA-senstive leukemia cells. A very low concentration of JQ1, a thienotriazolodiazepine and a potent BRD4/2/BET inhibitor, can efficiently re-sensitize the 5-AZA-resistant MDS/AML cell lines and completely reverse the drug resistance to 5-AZA, supporting the model of BRD4/2/BET-mediated 5-AZA-resistance in leukemia.