miR-128a and miR-130b determine lineage choice and leukemia-propagating cell identity in MLL-AF4+ acute leukemia

MLL-AF4+ leukaemia is the most common leukaemia in infants and is characterised by a dismal prognosis. The failure to improve treatment outcome together with a difficulty to model this disease in mice highlight a lack of knowledge on how the disease initiates in utero. Using our previously described pre-leukaemia model as an experimental platform, we have now identified miR-128a and miR-130b as essential co-drivers of MLL-AF4+ leukaemogenesis. Their individual overexpression in mouse Mll-AF4+ LSK cells was sufficient to generate an acute leukaemia with central nervous system infiltration, a serious clinical problem of this disease. Remarkably, while the overexpression of miR-128a results in a pro-B ALL, the overexpression of miR-130b produces an acute mixed myeloid/BCP lineage phenotype. Furthermore, while miR-130b+ leukaemia is propagated by LMPPs, miR-128a+ leukaemia is maintained by a unique ckit+IL7R+ population. Both leukaemias express key signature genes associated with MLL-AF4+ leukaemia and rely on the continuous expression of the miRNA for their maintenance. Furthermore, we have discovered 2 novel tumour suppressors as downstream targets of miR-130b and miR-128a.

Publication History

Article published online:
13 May 2020