Research Projects

The origin and biology of AML stem cells

Cancer has been historically viewed as a stem cell disease, in which stem cells with inherent self-renewal property are the putative targets for accumulation of multiple genetic mutations leading to overt diseases. However, we and others have shown that while murine haematopoietic stem cells (HSCs) were the origin of the leukaemic stem cells (LSCs) that give rise to the acute biphenotype leukaemia, 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 (Cozzio et al., 2003; Huntly et al., 2004; So et al., 2003a) (Figure 1). In the latter, leukaemia associated transcription factors (LATFs) induce epigenetic reprogramming and confer self-renewal properties to otherwise short-lived progenitor cells. However, it is not clear what are the biological and functional differences of the LSCs derived from these distinctive cellular targets. Also while these proof of principle studies suggest that AML stem cells can be derived from HSCs or progenitors, it remains largely unclear if the similar principle can also be applied to human AML stem cells.

Primary Focus:

  • 1) To functionally define and identify the potential origins of human AML stem cells; and
  • 2) To define and characterize the impact of cells-of-origin in governing the biology of the resultant LSCs.

 

Figure 1
Figure 1. CSCs Models in MLL leukaemia.  Top: normal hematopoiesis; Bottom left: CSCs model for multi-lineage leukaemia; Bottom right: CSCs model for AML.  MLL fusion indicates the initiating event taken place in various cell origins (e.g., HSCs, CMP and GMP).  ABL: acute biphenotypic leukaemia; ALL: acute lymphoid leukaemia; AML: acute myeloid leukaemia. 

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