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

• Type of Material: Article
• Authors: Thomas B. Alexander, St Jude Childrens Research Hospital; Zhaohui Gu, St Jude Childrens Research Hospital; Ilaria Iacobucci, St Jude Childrens Research Hospital; Kirsten Dickerson, St Jude Childrens Research Hospital; John K. Choi, St Jude Childrens Research Hospital; Beisi Xu, St Jude Childrens Research Hospital; Debbie Payne-Turner, St Jude Childrens Research Hospital; Hiroki Yoshihara, St Jude Childrens Research Hospital; Mignon L. Loh, University of California San Francisco; John T Horan, Emory University; Barbara Buldini, University of Padua; Giuseppe Basso, University of Padua; Sarah Elitzur, Tel Aviv University; Valerie de Haas, Prinses Maxima Center; C. Michel Zwaan, Prinses Maxima Center; Allen Yeoh, National University of Singapore; Dirk Reinhardt, University of Klinikum; Daisuke Tomizawa, National Center for Child Health and Development; Nobutaka Kiyokawa, National Research Institute for Child Health and Development; Tim Lammens, Ghent University Hospital
• Language: English
• Date: 2018-10-18
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Springer Nature Limited. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-018-0436-0
• Title of Journal or Parent Work: Nature
• ISSN: 0028-0836
• Volume: 562
• Issue: 7727
• Start Page: 373
• End Page: +
• Grant/Funding Information: This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract No. HHSN261200800001E (to C.G.M. and Michael Smith Genome Sciences Centre).; This work was supported in part by the American Lebanese Syrian Associated Charities of SJCRH, Cookies for Kids Cancer (to H.I.), St. Baldrick’s Foundation Robert J. Arceci Innovation Award and Henry Schueler 41&9 Foundation (to C.G.M.), SJCRH Physician Scientist Training Program Fellowship (to T.B.A.), the National Cancer Institute grants P30 CA021765 (SJCRH Cancer Center Support Grant), Chair’s grant and supplement to support the COG ALL TARGET project), U10 CA98413 (to the COG Statistical Center), U24 CA114766 (to COG; Specimen Banking), and Outstanding Investigator Award R35 CA197695 (to C.G.M.).
• Keywords: ACUTE LYMPHOBLASTIC-LEUKEMIA; Science & Technology - Other Topics; CHILDREN; PROGNOSIS; Multidisciplinary Sciences; IDENTIFICATION; EXPRESSION; ACUTE MYELOID-LEUKEMIA; DNA-SEQUENCING DATA; LINEAGE; CLASSIFICATION; Science & Technology; LANDSCAPE
• Research Categories: Health Sciences, Oncology; Biology, Genetics; Biology, Cell

Abstract

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.