Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and 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 ZNF384 is 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 immunophenotypic heterogeneity 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 immunophenotypic diversity in vivo. These findings indicate that the cell of origin and 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 framework for future clinical trials of potential treatments for MPAL.

• MeSH
• Leukemia, Biphenotypic, Acute classification   genetics   pathology   MeSH
• Cell Lineage genetics   MeSH
• Phenotype MeSH
• Genetic Variation genetics   MeSH
• Genome, Human genetics   MeSH
• Genomics MeSH
• Immunophenotyping MeSH
• Humans MeSH
• Models, Genetic MeSH
• Mutation genetics   MeSH
• DNA Mutational Analysis MeSH
• Neoplastic Stem Cells immunology   metabolism   pathology   MeSH
• Trans-Activators genetics   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Trans-Activators MeSH
• ZNF384 protein, human MeSH Browser

• Keywords
• IncRNA H19 regulation, LIN28B overexpression, pediatric leukemia,
• MeSH
• Child MeSH
• Infant MeSH
• Leukemia genetics   metabolism   pathology   MeSH
• Humans MeSH
• Adolescent MeSH
• Neoplasm Proteins biosynthesis   genetics   MeSH
• Child, Preschool MeSH
• RNA-Binding Proteins biosynthesis   genetics   MeSH
• Gene Expression Regulation, Leukemic * MeSH
• RNA, Long Noncoding genetics   metabolism   MeSH
• RNA, Neoplasm genetics   metabolism   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Letter MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• H19 long non-coding RNA MeSH Browser
• LIN28B protein, human MeSH Browser
• Neoplasm Proteins MeSH
• RNA-Binding Proteins MeSH
• RNA, Long Noncoding MeSH
• RNA, Neoplasm MeSH