Understanding the role of ontogeny for the development of MLL-AF9 infant leukaemia

MLL fusions disproportionately cause infant leukaemia, where MLL-AF9 generates AMKL, AML and B-ALL, despite causing only AML in adults. We used a doxycycline-inducible mouse model of MLL-AF9 expression to show that following in utero induction from E12.5, mice develop AML from birth to 3 weeks of age; a faithful human-like latency. Transplantation of E14.5 foetal liver (FL) HSPCs into adult recipients showed AML that is most aggressive in HSC/MPP and least in GMP. Transplantation of LMPP in neonates gave an expansion of B220+ CD19+ blasts that were eventually outcompeted by an expanding CD11b+ population that caused AML, demonstrating microenvironment influence in leukaemia. Parallel experiments in methylcellulose assays with FL and adult BM HSPCs found that in myeloid conditions, FL HSC/MPP were most able to generate CD41+ c-Kit+ blasts, suggesting a foetal origin for AMKL. In B-lymphoid culture, FL HSPCs had a significantly higher ability to self-renew following replating, with LMPP and CLP proliferating with a pro-B lymphoid phenotype. In summary, we found FL HSPC origins for MLL-AF9 infant leukaemias and an in-vivo infant AML model, which may inform rationale for drug discovery.

Publication History

Article published online:
17 May 2022