PROJECT SUMMARY High expression of the transcriptional co-activator Meningioma-1 (MN1) is common in AML, and associated with a poor prognosis. Forced expression of MN1 in murine hematopoietic progenitors induces an aggressive leukemia. We recently discovered that the primary interaction partner of MN1 is the BAF nucleosome- positioning complex. MN1 stabilizes BAF on chromatin. MN1 binding is associated with sustained active enhancer chromatin at enhancers regulating a hematopoietic stem/progenitor program. We hypothesize that MN1 stabilizes promoter-enhancer contacts at these sites through a BAF dependent mechanism. The goal of this project is to uncover the molecular mechanism of MN1-mediated leukemic transformation. A better understanding of how MN1 causes leukemia may identify opportunities for targeted therapies in a patient population who is failing conventional AML therapy.

PROJECT NARRATIVE In 2014 there were an estimated 20,000 new cases of acute myeloid leukemia (AML) resulting in over 10,000 deaths. 20-25% of AML have very high expression of a gene called Meningioma-1 (MN1), and most of these patients have a very poor prognosis. We propose that MN1 causes leukemia by interfering with appropriate gene regulation, and that identifying critical mechanisms involved in this process may generate a path towards developing specific inhibitors that could help treat AML.