PROJECT SUMMARY High expression of the intrinsically disordered protein 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. Intriguingly, MN1’s entire coding frame is disordered. We hypothesize that MN1 causes AML by overstabilizing transcriptional hubs by increasing multi- valent, low affinity interactions that result in high local concentrations of BAF and early hematopoietic transcription factors. 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 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, thus substantially contributing to over 10,000 deaths from AML/year in the US. We hypothesize that MN1 causes AML primarily by stabilizing gene regulatory hubs via intrinsically disordered, “sticky” domains. Dissecting how MN1 achieves this will yield fundamental insights into gene regulation and may point the way towards novel and innovative therapies targeting intrinsically disordered domains.