Researchers find molecular trigger to drug sensitivity of leukaemia
London – Leukaemic stem cells can be reversed to a pre-leukaemic stage by suppressing a protein called beta-catenin found in the blood. A research group headed by Professor Eric So at King's College London also reported that advanced leukaemic stem cells, which had become therapy resistant, could be 're-sensitised' by suppressing the same protein (Cancer Cell, 13 December). The haematologists believe the findings represent a 'critical step forward' in the search for more effective treatments for aggressive forms of leukaemia.
The scientists looked at leukaemic stem cells found in types of leukaemia that involve mutations of the MLL gene. This accounts for around 70 per cent of infant leukaemias and 10 per cent of adult acute leukaemias. The prognosis for this type of leukaemia in children is not good – only 50 per cent survive past two years after receiving standard anti-leukaemia treatment.
To understand how the disease develops, the scientists compared pre-leukaemic stem cells (which do not always develop into leukaemia) with leukaemic stem cells in vitro and in vivo. In a mice model, development of pre-leukaemic into leukaemic stem cells correlated with activation of beta-catenin. Suppression of beta-catenin in leukaemic stem cells reduced leukaemic cell growth, delayed the onset of leukaemia and reversed the stem cells to a pre-leukaemic stage. Furthermore, when beta-catenin was completely inactivated in mice with pre-leukaemic cells, the mice did not develop leukaemia (albeit they carried MLL mutations).
The study also revealed that beta-catenin seems to mediate drug resistance of leukaemic stem cells. When So et al. suppressed expression of beta-catenin in human MLL leukaemic cells they became sensitive again. The researchers will now determine the molecular mechanism by which beta-catenin mediates its effects.