Sunday, May 18, 2025
5/18/2025
Assessing lineage infidelity, oncogenic cooperativity and dependency in RUNX1-mutant acute myeloid leukemia - PROJECT SUMMARY/ABSTRACT RUNT-related transcription factor 1 (RUNX1) is a master regulator of hematopoiesis and leukemogenesis. RUNX1 mutations are identified in 10-20% of patients with acute myeloid leukemias (AML). RUNX1-mutant AML is characterized by chemoresistance and poor prognosis. Lineage infidelity is prevalent in RUNX1-mutant AML and has been proposed as a potential mechanism of therapeutic resistance. However, the mechanisms by which RUNX1 mutations confer lineage infidelity in AML and the specific contribution of lineage infidelity to the pathogenesis of RUNX1-mutant AML remain poorly understood. Leukemogenic RUNX1 mutations may possess potential mutant-specific functionalities in leukemogenesis and lineage specification. NRAS mutations are the most common co-mutated genes in RUNX1-mutant AML exhibiting lineage infidelity, suggesting that NRAS mutations cooperate with pathogenic RUNX1 mutations to promote leukemogenesis and lineage infidelity. Current preclinical models including inducible Runx1 null mice and germline Runx1 R174Q mutations are not ideally suited to test this hypothesis. In this proposal, we will utilize a novel inducible, reversible Runx1R174Q allele, alone or together with cooperating Nras disease alleles. This will allow us to characterize the mutant-specific functionalities of RUNX1, the impact of comutations on leukemic transformation and lineage infidelity, and address the requirement for RUNX1 mutations in leukemia initiation and maintenance. The specific aims of this project are: 1) Characterize lineage infidelity, genetic heterogeneity and their prognostic relevance in RUNX1-mutant AML. 2) Determine the mechanisms by which Runx1R174Q and Runx1R174Q + NrasG12D induce leukemogenesis and lineage infidelity. 3) Investigate the necessity of Runx1R174Q mutations in disease initiation and maintenance. These studies will lead to better understanding of disease mechanisms and new modes of therapy, which will also shape the focus of my future independent lab. Wenbin Xiao, MD, PhD, an Assistant Member at MSKCC, will conduct this project as part of a 4-year career development plan, dedicating 75% of his time to research with remainder spent on clinical work. Wenbin is mentored by Dr. Ross Levine, a world expert in hematologic malignancies. He is also advised by Drs. Omar Abdel-Wahab, Kristian Helin and Richard Koche at MSKCC, and Dr. Ulrich Steidl at Albert Einstein College of Medicine. He will collaborate with Dr. Andriy DerKach and Dr. Elli Papaemmanuil both at Department of Bio- Statistics of MSKCC. Wenbin’s training will include gaining technical laboratory skills, knowledge in the novel leukemia mouse model with dual recombinases, knowledge in the epigenetic regulation, and formal training in bioinformatics. In the short term, the project goal is to publish two papers on the findings from this research. In the long term, the goal is for developing a research program and obtaining R01 funding to become an independent laboratory investigator in hematologic malignancies.
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).