Grant: Project Grant

Acute myeloid leukemia (AML) is characterized by the uncontrolled growth of immature bone marrow cells. Across Canada, every year there are approximately 1500 new cases of AML and 1000 deaths, making it one of the deadliest cancers. For the past 40 years, the primary treatment for AML has been induction chemotherapy. However, about one-third of AML patients do not respond to treatment; these chemotherapy-resistant (also known as refractory) AML patients have few therapeutic options. Moreover, there had been no way to identify refractory AML patients before they failed treatment, which weakens those patients while serving to potentially make their cancer worse. We recently discovered an important reason why most AML patients fail induction chemotherapy - they lose the expression of a gatekeeper protein known as MTF2. We found that the protein MTF2 functions to tightly regulate how cells respond to the DNA damage caused by chemotherapy. Our work led to an ongoing clinical trial to identify chemoresistant AML and test a novel therapeutic. Now we propose to uncover the role of MTF2 in regulating the cellular response to chemotherapy drugs to understand why MTF2-deficient AML cells are chemoresistant and identify potential therapies to overcome resistance. Normally, induction chemotherapy drugs induce sufficient DNA damage to prevent DNA replication, triggering cell death. However, MTF2-deficient chemoresistant cells continue to proliferate following chemotherapy treatment. We will use complementary approaches to tease apart DNA repair in chemotherapy-sensitive versus chemoresistant AML cells. We will determine if MTF2 regulates the DNA repair at the level of DNA repair protein expression and/or if MTF2 regulates DNA repair directly by recruiting specific repair complexes to sites of DNA damage. In performing these experiments, we predict that we will identify therapeutic targets and additional biomarkers of chemoresistance.