Alexander T.B.Gu Z.Iacobucci I.Dickerson K.Choi J.K.Xu B.Payne-Turner D.Yoshihara H.Loh M.L.Horan J.Buldini B.Basso G.Elitzur S.de Haas V.Zwaan C.M.Yeoh A.Reinhardt D.Tomizawa D.Kiyokawa N.Lammens T.De Moerloose B.Catchpoole D.Hori H.Moorman A.Moore A.S.Hrusak O.Meshinchi S.Orgel E.Devidas M.Borowitz M.Wood B.Heerema N.A.Carrol A.YUNG-LI YANGSmith M.A.Davidsen T.M.Hermida L.C.Gesuwan P.Marra M.A.Ma Y.Mungall A.J.Moore R.A.Jones S.J.M.Valentine M.Janke L.J.Rubnitz J.E.Pui C.-H.Ding L.Liu Y.Zhang J.Nichols K.E.Downing J.R.Cao X.Shi L.Pounds S.Newman S.Pei D.Auvil J.M.G.Gerhard D.S.Hunger S.P.Inaba H.Mullighan C.G.2021-01-062021-01-0620180028-0836https://www.scopus.com/inward/record.uri?eid=2-s2.0-85055205297&doi=10.1038%2fs41586-018-0436-0&partnerID=40&md5=4a1b9e4662a91a3b8fd389136d4e32fahttps://scholars.lib.ntu.edu.tw/handle/123456789/538620Mixed 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. ? 2018 Springer Nature Limited. All rights reserved.[SDGs]SDG3cyclin dependent kinase inhibitor 2B; transactivator protein; ZNF384 protein, human; cell; genetic analysis; genomics; heterogeneity; phenotype; acute leukemia; acute lymphoblastic leukemia; animal experiment; animal model; animal tissue; Article; CDKN2B gene; CEBPA gene; cell lineage; clinical article; controlled study; female; gene; gene frequency; gene function; gene identification; gene mutation; gene rearrangement; genetic variation; genome analysis; heredity; human; human cell; human tissue; mixed phenotype acute leukemia; mouse; mutational analysis; nonhuman; phenotype; phenotypic plasticity; phenotypic variation; predictive value; priority journal; ZNF384 gene; acute biphenotypic leukemia; biological model; cancer stem cell; classification; dna mutational analysis; genetics; genomics; human genome; immunology; immunophenotyping; male; metabolism; mutation; pathology; phenotype; Cell Lineage; DNA Mutational Analysis; Female; Genetic Variation; Genome, Human; Genomics; Humans; Immunophenotyping; Leukemia, Biphenotypic, Acute; Male; Models, Genetic; Mutation; Neoplastic Stem Cells; Phenotype; Trans-Activatorsjournal article10.1038/s41586-018-0436-0302093922-s2.0-85055205297