Project 462899

Acute Myeloid Leukemia (AML) typically responds well to initial therapies, but relapse is common due to drug resistance. AML cells in the circulating blood are usually cleared well, but resistant cells remain in the bone marrow. How the bone marrow contributes to cancer drug resistance at the molecular level is not well understood. We have discovered that all leukemias typically silence the YAP and TAZ genes. However, upon contact with blood vessel cells in the bone marrow they activate expression of these proteins. We hypothesize that YAP and TAZ induction changes the character of AML cells so that they resist drug treatments. We will examine YAP and TAZ induction in AML cell lines and primary patient AML samples, in response to contact with blood vessel cells and therapeutic drugs. We will also ask whether YAP and TAZ are required and sufficient for drug resistance. Finally, we will deduce how YAP and TAZ might confer resistance at the molecular level. We anticipate that these data will open new avenues to block drug resistance in AML and thus improve outcomes for patients.