Cytokine receptor signalling is essential for cell survival, proliferation and subsequent differentiation of haematopoietic stem cells (HSCs). Cytokines control development of haematopoietic progenitors into cells of the myeloid, lymphoid and erythroid linages by stimulating cell cycle progression, proliferation and differentiation as well as by inhibiting apoptosis.
Interleukin-3 (IL-3) and Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) belong to the family of cytokines that share the β common (βc) chain as part of their cognate receptors. The α chain on the other hand is specific to each cytokine receptor. Binding of cytokine to its specific receptor results in the activation of Janus kinase 2 (JAK2), a receptor-associated kinase essential for cytokine receptor signalling. This leads to the phosphorylation of the βc chain, which results in the activation of multiple kinase signalling pathways, including the JAK/STAT, Ras-MAP kinase (MAPK) and PI3-kinase/AKT pathways. In this signalling network the IκB Kinase (IKK) complex plays an important role as a downstream signalling hub. Defects in the control of these kinase signalling pathways are known to promote leukaemia development.
When IL-3 or GM-CSF is removed, cytokine-dependent haematopoietic cells, such as myeloid progenitors, undergo cell death by a mechanism that is regulated by the Bcl-2 family of apoptosis regulators. Our laboratory has recently discovered a novel role for the IκB Kinase (IKK) complex in regulating the activity of certain Bcl-2 family members in myeloid cells. We find that activation of IKK by IL-3 downregulates the levels of the pro-apoptotic BH3-only protein Puma, a critical initiator of apoptosis.
Using immortalised growth factor (IL-3 or GM-CSF) dependent myeloid progenitor cells (FDMs), that absolutely require these cytokines for survival and proliferation, we aim to determine how IL-3 mediated IKK activation promotes the survival of myeloid cells and what role this process may play in leukaemia development.