Self-renewal pathways in hematopoietic and cancer stem cells

Leukaemogenesis Team

Section: Section of Haemato-Oncology

Self-renewal is not only a feature that distinguish cancer stem cells (CSCs) from their differentiating cancer progenies but also the most critical property associated with CSCs to sustain their immortal growth. Recent studies using mouse model provide overwhelming amount of evidence indicating the functional conservation of the self-renewal pathways shared by both the normal and cancer stem cells. It has been speculated that from an evolutionary perspective stem cells, are inherently as risk and clonal escape, cancers being in this respect a trade off against the huge advantage of regulated self-renewal. Consistently we and others have shown that haematopoietic stem cells (HSCs) originate the CSCs that give rise to the acute biphenotype leukaemia, although both HSCs and early myeloid progenitors (CMP, common myeloid progenitor; and GMP, granulocyte-myeloid progenitor) can be transformed by MLL or MOZ oncoproteins resulting in AML (So et al., 2003a).  Self-renewal signaling pathways shared by normal and cancer stem cells or resurrected in immature progenitors are key to this process. Among them, the highly evolutionarily conserved Hox pathways (discussed in a previous section) regulated by Polycomb group (PcG) and trithorax group (trxG) proteins emerge as the major pathways involved in self-renewal of both normal and cancer stem cells. Currently we are interested in understanding the regulation and potential cross-talked between the MLL/Hox and Bmi-1/Ink4a mediated pathways in both normal and malignant haematopoiesis.

Our primary focuses:

• Explore the roles of Bmi-1 in distinctive forms of haematopoietic malignancies induced by different oncoproteins
• Investigate the potential cross talk between MLL/Hox and Bmi-1/ink4a pathways in mediating self-renewal of both normal haematopoietic stem cells and cancer stem cells

This work is supported by the Institute of Cancer Research (ICR).