The genetic basis and cell of origin of mixed phenotype acute leukaemia

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloidand lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/ myeloid(T/M) and B/ myeloid(B/M), are genetically distinct. Rearrangement of ZNF384is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypicheterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypicdiversity in vivo. These findings indicate that the cellof originand founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed frameworkfor future clinical trials of potential treatments for MPAL.