Novel Therapeutic Target in Leukemia Stem Cells

Progress in the treatment of children diagnosed with acute myeloid leukemia (AML) has been significant, but hard fought, through intensification of the dosing and timing of therapy and better supportive care for the resulting complications.  Despite intensive therapy, often including stem cell transplantation, almost half of the children diagnosed with AML will succumb to refractory or relapsed disease driven by resistant leukemic stem cells (LSC). The resistant LSC lies at the root of failure to achieve remission, and failure to completely eradicate the LSC leads to eventual relapse. Through interactions with its bone marrow niche, the LSC remains quiescent -- it does not cycle rapidly or differentiate -- and enjoys enhanced survival and resistance to chemotherapy. Therefore, targeting the leukemic stem cell has become an intense focus of interest within leukemia research. One strategy is to target the LSC interaction with its protective microenvironment in the bone marrow thereby rendering the LSC more vulnerable to therapy.  This project highlights our recent advances in leukemia modeling and the role of a protein involved in stem cell adhesion in the bone marrow, the Cdc42 protein.  If effective, inhibition of Cdc42 could be evaluated in clinical trials, particularly in concert with high dose chemotherapy in patients undergoing stem cell transplantation.