Mapping Stem Cell Dependencies in Cancer Heterogeneity and Therapy Resistance

Our research focuses on the signals that control stem cell self-renewal and how these signals are hijacked in cancer. Using a series of genetic models, we have studied how classic developmental signaling pathways play key roles in hematopoietic stem cell growth and regeneration and are dysregulated during leukemia development. Through this work we have identified Hedgehog and Wnt signaling, and more recently the cell fate determinant Musashi, as critical players in driving progression of hematologic malignancies and as targets for therapy. To search for new regulators of myeloid leukemia, we have carried out a focused screen of surface molecules that may enable leukemia cells to receive supportive cues from the microenvironment. This screen identified key new adhesion signals that are critical to leukemia growth, drug resistance and dissemination. Using high resolution in vivo imaging we have mapped how these mediate the interactions that leukemia cells make within their microenvironment. To complement this focused screen, we have also carried out a genome wide CRISPR screen to more generally define the biological determinants of myeloid leukemia establishment and propagation. This screen identified a large number of new genes and programs critically required for leukemia, including those essential for chromatin remodeling and spliceosomal assembly. Among these, RNA binding proteins (RBPs) in general, and the chromatin binding sub-family of RBPs in particular, emerged as key new dependencies of myeloid leukemia. The talk will focus in part on these new regulators.