Acute myeloid leukaemia (AML) is a devastating disease with limited treatment options. Understanding the biology of the leukaemic stem cell (LSC), thought to cause disease relapse, is key to therapeutically targeting this cell population and preventing re-emergence of leukaemia. The interleukin-3 receptor α-chain (IL-3Rα), a biomarker for AML LSC, displays increased expression on AML LSC compared to normal haematopoietic stem cells. However, the functional significance of this elevated expression remains unknown. We hypothesise that high IL-3Rα expression is selected to provide cells with survival and/or proliferative advantages.
Our in vitro studies supported our hypothesis demonstrating, that high levels of IL-3Rα promote increased proliferation, repress apoptosis and amplify signalling in response to low doses of IL-3. Unexpectedly, our in vivo models revealed contrasting findings. In competitive reconstitution assays, murine foetal liver cells transduced to express an empty vector (EV) control or high muIL-3Rα were transplanted into irradiated recipient mice. While the EV cells engrafted with high efficiency, the cells expressing high muIL-3Rα were unable to reconstitute the bone marrow, implying elevated IL-3Rα prevented cell engraftment. Mechanisitically, over-expressed IL-3Rα appears to prevent effective homing of stem cells into the bone marrow niche and alter chemokine signalling. While high IL-3Rα expression is negatively selected for in normal haematopoietic progenitor cells in a transplant model, and its over-expression alone does not initiate AML, we propose that IL-3Rα plays a context-dependent role in the development and progression of leukaemia. We will present novel data to elucidate the mechanism of the engraftment defect and the in vivo role of IL-3Rα in AML. This study identifies a new function of increased IL-3Rα expression on haematopoietic cells. As interactions between the bone marrow microenvironment and the LSC are emerging as a key factor of LSC survival, this new role for IL-3Rα provides an alternate pathway to target LSC.