Mechanisms of Chemotherapy Resistance in Acute Myeloid Leukemia

Background:

Use of risk-directed combination chemotherapy and stem cell transplantation can now cure many patients with acute myeloid leukemia. However, the outlook for those who relapse or have unfavorable features remains dire, underscoring the major unmet need for improved therapies. To identify new therapeutic targets, we carried out a functional proteomic screen using high-accuracy mass spectrometry of primary AML cells. This work led to the discovery of specific signaling cascades associated with therapy resistance. In particular, we have identified aberrant phosphorylation of MEF2C, a master transcriptional regulator, that drives aberrant AML cell growth and survival.

Project Goal:

Studies planned as part of this proposal will investigate the function of MEF2C signaling in AML leukemogenesis using a battery of biochemical and cell biological experiments, including genetically-engineered mouse models in vivo. These studies are poised for immediate translation into improved anti-leukemia therapies, such as kinase inhibition for targeting leukemogenic MEF2C signaling. This work is bolstered by the use of innovative proteomics tools which we have developed, as well as access to a collection of clinical-grade kinase inhibitors, thus enhancing its feasibility and translational potential. This research program should accelerate progress toward the long-term goal of rational combination therapy of AML.