3051 – IDENTIFYING THE CELL OF ORIGIN IN MLL-AF9 INFANT LEUKAEMIA

Abstract

MLL rearrangements are the predominant cause of acute infant leukaemias, which initiate in utero within foetal HSPCs and distinctly lack additional cooperating mutations. Strikingly, MLL-AF9 causes an AML or B-ALL, but in adults almost exclusively an AML. Thus, by understanding the contribution from the foetal cell of origin, we can explain differences between patients with respect to disease initiation, progression and outcomes. We utilised inducible MLL-AF9 expression to explore AML and B-ALL initiation from foetal and adult murine HSPCs. MLL-AF9 imparts distinct lineage, proliferation and self-renewal outputs within and between foetal and adult HSPC populations. In contrast to adult HSPCs, MLL-AF9 generated significant increases in lymphoid output under lymphoid conditions across foetal HSPC in vitro, even overriding CMP myeloid bias for B-lymphoid output, highlighting the specific nature of infant biology. HSC/MPP and LMPP consistently gave rise to a pro-B phenotype, suggesting these as cells of origin for the clinically dismal infant pro-B ALL. In AML, transplantation of HSC/MPP causes the most aggressive disease marked by shortest latency and invasive nature. Interestingly, in myeloid assays, foetal HSC/MPP and LMPP display an initial delay in proliferation, unlike CMP and GMP, which proliferate through a foetal-specific phenotype of CD11b+ blasts at first plating. Adult CMP do not replicate the proliferative phenotype of foetal CMP, highlighting the differences in disease initiation between developmental stages. An MLL rearrangement represents the worst prognostic factor for B-ALL, and in AML a description of which foetal cells can initiate disease is lacking. Given the prevalence of unfavourable prognostic factors, defining how foetal blood cell biology shapes the aetiology of infant leukaemia will inform rationale for drug discovery and therapy applications.