Acute myeloid leukemias (AML) arise from the uncontrolled clonal expansion of hematopoietic progenitor cells. Different subtypes of AML are associated with specific chromosomal translocations. For example, the subtype M4Eo is associated with the chromosome 16 break-and-join inversion of the genes that code for the fusion gene CBFb-MYH11. Within subtypes, additional mutations have also been found in other genes including Ras, p53, and NFl. These mutations could play a role in CBFB-MYH11 mediated AML .We generated the Cbfb-MYH11 knock-in mouse, mimicking the presence of CBFb-MYH11 in human AML-M4Eo. We have shown that Cbfb-MYH11 plays a role in leukemogenesis by blocking hematopoietic differentiation. We hypothesize that AML is the result of a process that involves two-events: 1. The creation of a fusion gene that alters hematopoietic stem cell differentiation and 2. the introduction of one or more other mutations that are associated with apoptosis and/or proliferation. To test these hypotheses we will identify genes that synergize with Cbfb-MYH11 to develop AML. We will first combine retroviral insertional mutagenesis in our knock in mice with inverse PCR to identify genes altered in AML (Aim 1). We will then use retroviral transduction of identified genes and transplantation experiments to test for a transforming role of these genes. As an alternative approach to test our hypotheses, we will use genetic crosses and retroviral transduction experiments to evaluate the functional interactions between Ras associated genes and Cbfb-MYH11 in AML development (Aim 2). Our long-term goals are to understand the genetic mechanisms that determine AML, and to provide targets for the design of improved therapies.
