Identifying Mechanisms of Chemoresistance Induced by MECOM in Primary-Refractory Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is an aggressive blood cancer that is expected to affect ~20,800 new patients and cause ~11,200 deaths in the US in 2024. Most AML patients go into an initial remission after treatment with chemotherapy, but ~25% of patients do not respond, and are referred to as “Primary-Refractory” AML (P-R AML). These patients have few treatment options, and almost all will die within 1 year of diagnosis. As a result, there is an urgent clinical need to identify new therapies to treat P-R AML patients; however, little is known about the what causes P-R AML, which has slowed drug development for these patients. To develop a better understanding of this disease, we are performing an in-depth study of P-R AML patient samples to define the DNA mutations, gene expression profiles, proteins, metabolites, and lipids that may be relevant for why these patients do not respond to treatment. This data has shown that AML cells from many P-R patients express high levels of MECOM mRNA, and these AMLs exhibit unique patterns of mRNA, protein, and metabolite abundance. To determine which of these features are caused by MECOM directly, we will use a genetically engineered mouse model that allows us to activate Mecom expression in blood cells. We will perform in-depth analysis of these mice to determine the impact of MECOM overexpression on genes, proteins, metabolites, and lipids in non-leukemic blood cells, and in AMLs that develop in these mice. This mouse model may allow us to determine how MECOM causes chemotherapy resistance, and will help us to identify pathways that could potentially be targetable with novel approaches. We will also determine whether MECOM could be a direct therapeutic target in P-R AML patients, by testing whether MECOM inactivation in mouse and human AMLs slows or stops AML cell growth. If successful, these studies could lay a foundation for understanding the causes of P-R AML, and hopefully could lead to the development of novel therapies to improve the lives of these patients.