The overall goal of this ROO grant application is to identify and characterize the early events in inv(16) associated acute myeloid leukemia (AML), and generate preliminary data and exciting new directions of inquiry for future R01 grant applications . My long-term goal is to establish myself as an independent investigator in the field of myeloid leukemia, with a focus on inv(16) associated AML. Inv(16) creates a fusion gene between the transcription factor CBFB, and the gene encoding smooth muscle myosin heavy chain, MYH11. The resulting fusion gene, CBFB-MYH11 encodes the protein CBFP-SMMHC. Based on my previous research, I hypothesize that expression of CBFB-MYH11 induces an abnormal population of leukemia initiating cells (LIC) through distinct changes in gene expression. Understanding the mechanism that generates these LICs may provide new drug targets for the treatment of inv(16) AML as well as novel insights into normal myeloid development. Thus, I propose to (Specific Aim 1) characterize and isolate the Cbfb-MYH11+ leukemia initiating population;(Specific Aim 2) analyze potential mechanisms mediating Cbfb-MYH11 induced changes in gene expression. Completing these Specific Aims w/ill provide: (i) an improved understanding of CBFB-MYH11 LICs, (ii) potential mechanisms of CBFB-MYH11 induced leukemogenesis, (iii) new research directions that will serve as the basis for future R01 grant applications.
lnv(16) AML is classified as prognostically goo. Even so, the long-term survival of patients with inv(16) AML is only 40%. Therefore, these is a great need to develop new and better treatments for inv(16) AML. However, this requires a thorough understanding of the mechanism of inv(16) AML, and the most relevant cell type, the LIC. This project will address both these topics, with the aim at identifying targets for future drug
|Richter, Lisa; Wang, Yiqian; Hyde, R Katherine (2016) Targeting binding partners of the CBF?-SMMHC fusion protein for the treatment of inversion 16 acute myeloid leukemia. Oncotarget 7:66255-66266|
|Hyde, R K; Zhao, L; Alemu, L et al. (2015) Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice. Leukemia 29:1771-8|
|Kamikubo, Yasuhiko; Hyde, R Katherine; Zhao, Ling et al. (2013) The C-terminus of CBF?-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis. Blood 121:638-42|