Research Projects

Self-renewal pathways critical for normal and leukaemic stem cells

Self-renewal is an important feature that distinguishes stem cells (both normal and malignant) from their short-lived progenitors, and also the most critical property associated with LSCs for sustaining their immortal growth. 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 recent studies provide overwhelming amount of evidence indicating the functional conservation of the self-renewal pathways shared by both the normal and cancer stem cells. However, we and others also discovered a number of self-renewal pathways such as canonical Wnt/-catenin (Wang et al., 2010; Yeung et al., 2010) uniquely required for LSCs but not normal HSCs (Zeisig et al., 2012). In addition to the evolutionarily conserved PI3K/PTEN pathways (Figure 4), we also reveal complicated crosstalk between Polycomb group (PcG) and trithorax group (trxG) proteins in regulating self-renewal of both normal and cancer stem cells (Smith et al., 2011; Zeisig et al., 2011) (Figure 5). Identification of the molecular pathways underlying self-renewal will lead to important insights into stem cell biology, and also facilitates the development of effective therapeutic strategies.

Primary Focus:

  • 1) To dissect the regulation and potential cross-talked between Polycomb group (PcG) and trithorax group (trxG) proteins in both normal and malignant haematopoiesis.
  • 2) To study the roles of PI3K/PTEN/PDK pathways in maintenance of normal and leukaemic stem cells.
Figure 4. PI3K/PTEN/PDK mediated pathways in normal and malignant hematopoiesis.  PI3K is frequently activated in acute leukemia and inactivation of PTEN leads to depletion of HSCs and acute leukemia in mouse model.  Foxo members critical for self-renewal of normal hematopoietic stem cells are fusion partners to MLL in acute leukemia, which can be suppressed by inhibition of GSK3.
Figure 5
Figure 5. Potential cross talk between Bmi1/Ink4 and MLL/Hox mediated self-renewal.Loss of Bmi1 leads to self-renewal defects in hematopoietic and leukemic stem cells as a result of activation of Ink4a/Arf loci.  However, MLL mediated Hox expression may compensate for loss of Bmi1 in mediating self-renewal. 

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