Monday, April 29, 2024
4/29/2024
Project Summary Chromosomal translocations producing oncogenic fusion proteins are common drivers of many types of cancer, including leukemia. Translocations involving the Nucleoporin 98 (NUP98) gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). NUP98-fusion proteins interact with the mixed-lineage leukemia (MLL1) chromatin modifying enzyme, and MLL1 is a molecular dependency in NUP98-rearranged (NUP98-r) AML. I recently showed that targeting the interaction between MLL1 and its binding partner Menin is therapeutically effective in NUP98-r AML. Menin-MLL1 inhibition using a small molecule VTP50469 simultaneously represses pro-leukemogenic genes and upregulates markers of myeloid differentiation. The overarching goal of this proposal is to define the mechanism by which the NUP98-fusion-Menin-MLL1 chromatin complex maintains a transcriptionally active chromatin state at pro-leukemogenic loci. I will investigate the hypothesis that NUP98-fusion proteins directly exert transcriptional control of a stem cell-associated gene expression program via their association with dynamic chromatin regulatory complexes. I have established a novel NUP98-r murine leukemia model in which NUP98-fusion proteins can be specifically and rapidly degraded by small molecules such as dTAG-13. I will use this model to define the immediate changes in gene expression and chromatin state that occur upon NUP98-fusion degradation. Next, I will define the impact of NUP98-fusion protein degradation on AML cellular hierarchies at single cell resolution in vivo. (Aim 1). I will determine the mechanism by which pro-leukemogenic genes are epigenetically silenced upon degradation or displacement of NUP98- fusion proteins. Based on preliminary CRISPR screen results, I hypothesize that silencing of pro-leukemogenic genes by the non-canonical polycomb repressive complex 1.1 (PRC1.1) is necessary for halting self-renewal of NUP98-r leukemia. I will define the role of PRC1.1 in NUP98-r leukemia by genetically inactivating each component of the complex using CRISPR. Next, I will determine how chromatin localization and enzymatic activity of PRC1.1 change upon degradation of NUP98-fusion proteins and upon Menin-MLL1 inhibition. Finally, I will determine whether loss of PRC1.1 function mediates resistance to Menin-MLL1 inhibition in vivo (Aim 2). As a physician-scientist dedicated to improving outcomes of patients with high-risk genetic subtypes of AML, my overall goal is to become an independent investigator and leader of my own laboratory studying oncogenic fusion proteins in leukemia. Since my previous research experience was mostly outside of this field, I require further training to gain deeper expertise in oncogenic fusion protein biology and epigenetics, as well as new skills in nascent transcriptomics, computational biology, and single cell methods. With the excellent mentorship of Dr. Scott Armstrong and my new co-mentor Dr. Brad Bernstein, the dynamic scientific environment of Dana-Farber Cancer Institute, and the financial support and protected time provided by the K08 award, I will be poised to develop into the leader of my own laboratory studying oncogenic fusion proteins in AML.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
