Hematopoietic stem cells (HSCs) have the ability to self-renew, allowing sustained lifelong production of all mature blood cells in vivo, and the production of progenitors that ensure the daily supply of all essential blood components. Given their unique properties, HSCs are widely used in transplantation to cure many blood diseases and malignancies, but unfortunately 40% of patients lack the required human leukocyte antigen (HLA)-matched donor. Because of their immaturity, cord blood (CB) grafts allow for multiple HLA mismatches and this permissiveness increases access to HSC transplants for more than 95% of patients. Moreover, when compared to other grafts, CB transplants are associated with less chronic graft-vs-host-disease (GVHD) and possibly with fewer incidences of relapse of the underlying malignancy when compared to other grafts. Currently, the main issue associated with CB transplantation is the low cell dose in cord blood units, which results in delayed or absence of engraftment, thereby increasing early mortality. As a result, there is great interest in molecules that expand HSCs.
Our lab, in collaboration with Anne Marinier’s group at IRIC, has identified the small molecule UM171, a compound that enhances the expansion of human CB HSCs (Fares et al., Science, 2014 and Pabst et al., Nature Methods, 2014). The benefits of UM171-mediated expansion of CB HSCs for HSC transplantation are currently being investigated as part of a phase I/II AML clinical trial. This research program aims to identify additional innovative strategies to further improve HSC expansion, to optimize HSC graft composition and translate these discoveries into clinical applications for AML treatment.