Identification of the cell of origin in infant MLL-AF9 leukaemia

MLL rearrangements are the predominant cause of acute infant leukaemias, which occur in utero within foetal HSPCs that distinctly lack additional cooperating mutations. Strikingly, MLL-AF9 causes an AML or B-ALL, but in adults almost exclusively an AML. Thus, the foetal cell of origin can explain differences between patients with respect to disease initiation, progression and outcomes. We utilised inducible MLL-AF9 expression to explore infant AML and B-ALL in foetal murine HSPCs. MLL-AF9 imparts distinct lineage, proliferation and self-renewal outputs within and between foetal and adult HSPCs. In contrast to adult HSPCs, MLL-AF9 generated significant increases in lymphoid output across foetal HSPC in CFU, even overriding CMP myeloid bias for B-ALL output, highlighting the specific nature of infant biology. HSC/MPP and LMPP gave rise to a pro-B ALL phenotype, suggesting these as cells of origin for the clinically dismal infant pro-B ALL. Fusion expression alone from E12.5 lead to a mixed-lineage AML with a median latency of 3 weeks, displaying the ability to model the human disease. Disease blasts retained lymphoid output, showing the lineage plasticity imparted by MLL-AF9.

Publication History

Article published online:
13 May 2020