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

Thomas B. Alexander, Zhaohui Gu, Ilaria Iacobucci, Kirsten Dickerson, John K. Choi, Beisi Xu, Debbie Payne-Turner, Hiroki Yoshihara, Mignon L. Loh, John Horan, Barbara Buldini, Giuseppe Basso, Sarah Elitzur, Valerie Haas, C. Michel Zwaan, Allen Yeoh, Dirk Reinhardt, Daisuke Tomizawa, Nobutaka Kiyokawa, Tim Lammens, Barbara Moerloose, Daniel Catchpoole, Hiroki Hori, Anthony Moorman, Andrew S. Moore, Ondrej Hrusak, Soheil Meshinchi, Etan Orgel, Meenakshi Devidas, Michael Borowitz, Brent Wood, Nyla A. Heerema, Andrew Carrol, Yung-Li Yang, Malcolm A. Smith, Tanja M. Davidsen, Leandro C. Hermida, Patee Gesuwan, Marco A. Marra, Yussanne Ma, Andrew J. Mungall, Richard A. Moore, Steven J. M. Jones, Marcus Valentine, Laura J. Janke, Jeffrey E. Rubnitz, Ching-Hon Pui, Liang Ding, Yu Liu, Jinghui Zhang, Kim E. Nichols, James R. Downing, Xueyuan Cao, Lei Shi, Stanley Pounds, Scott Newman, Deqing Pei, Jaime M. Guidry Auvil, Daniela S. Gerhard, Stephen P. Hunger, Hiroto Inaba () and Charles G. Mullighan ()
Additional contact information
Thomas B. Alexander: St. Jude Children’s Research Hospital
Zhaohui Gu: St. Jude Children’s Research Hospital
Ilaria Iacobucci: St. Jude Children’s Research Hospital
Kirsten Dickerson: St. Jude Children’s Research Hospital
John K. Choi: St. Jude Children’s Research Hospital
Beisi Xu: St. Jude Children’s Research Hospital
Debbie Payne-Turner: St. Jude Children’s Research Hospital
Hiroki Yoshihara: St. Jude Children’s Research Hospital
Mignon L. Loh: Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco
John Horan: Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Emory University School of Medicine, Department of Pediatrics
Barbara Buldini: Hemato-Oncology Division, University of Padova
Giuseppe Basso: Hemato-Oncology Division, University of Padova
Sarah Elitzur: Schneider Children’s Medical Center, Sackler Faculty of Medicine
Valerie Haas: Prinses Maxima Centre
C. Michel Zwaan: Prinses Maxima Centre
Allen Yeoh: Yong Loo Lin School of Medicine, National University of Singapore
Dirk Reinhardt: Universitäts-Klinikum
Daisuke Tomizawa: Division of Leukemia and Lymphoma, Children’s Cancer Center, National Center for Child Health and Development
Nobutaka Kiyokawa: National Research Institute for Child Health and Development
Tim Lammens: Ghent University Hospital
Barbara Moerloose: Ghent University Hospital
Daniel Catchpoole: The Children’s Hospital at Westmead
Hiroki Hori: Mie University
Anthony Moorman: Newcastle University
Andrew S. Moore: The University of Queensland Diamantina Institute & Children’s Health
Ondrej Hrusak: Charles University and University Hospital Motol
Soheil Meshinchi: Fred Hutchinson Cancer Research Center, Clinical Research Division
Etan Orgel: Children’s Hospital Los Angeles
Meenakshi Devidas: University of Florida
Michael Borowitz: Johns Hopkins Medical Institutions
Brent Wood: University of Washington
Nyla A. Heerema: The Ohio State University School of Medicine
Andrew Carrol: University of Alabama at Birmingham
Yung-Li Yang: National Taiwan University Hospital, College of Medicine, National Taiwan University
Malcolm A. Smith: Cancer Therapy Evaluation Program, National Cancer Institute
Tanja M. Davidsen: Center for Biomedical Informatics and Information Technology, National Cancer Institute
Leandro C. Hermida: National Cancer Institute
Patee Gesuwan: National Cancer Institute
Marco A. Marra: Michael Smith Genome Sciences Centre, BC Cancer Agency
Yussanne Ma: Michael Smith Genome Sciences Centre, BC Cancer Agency
Andrew J. Mungall: Michael Smith Genome Sciences Centre, BC Cancer Agency
Richard A. Moore: Michael Smith Genome Sciences Centre, BC Cancer Agency
Steven J. M. Jones: Michael Smith Genome Sciences Centre, BC Cancer Agency
Marcus Valentine: Cytogenetics Shared Resource, St. Jude Children’s Research Hospital
Laura J. Janke: St. Jude Children’s Research Hospital
Jeffrey E. Rubnitz: St. Jude Children’s Research Hospital
Ching-Hon Pui: St. Jude Children’s Research Hospital
Liang Ding: St. Jude Children’s Research Hospital
Yu Liu: St. Jude Children’s Research Hospital
Jinghui Zhang: St. Jude Children’s Research Hospital
Kim E. Nichols: St. Jude Children’s Research Hospital
James R. Downing: St. Jude Children’s Research Hospital
Xueyuan Cao: St. Jude Children’s Research Hospital
Lei Shi: St. Jude Children’s Research Hospital
Stanley Pounds: St. Jude Children’s Research Hospital
Scott Newman: St. Jude Children’s Research Hospital
Deqing Pei: St. Jude Children’s Research Hospital
Jaime M. Guidry Auvil: National Cancer Institute
Daniela S. Gerhard: National Cancer Institute
Stephen P. Hunger: Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania
Hiroto Inaba: St. Jude Children’s Research Hospital
Charles G. Mullighan: St. Jude Children’s Research Hospital

Nature, 2018, vol. 562, issue 7727, 373-379

Abstract: 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.

Keywords: Mixed Phenotype Acute Leukemia; Immunophenotypic Heterogeneity; Founder Lesion; St. Jude Children’s Research Hospital (SJCRH); Germline Samples (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (3)

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DOI: 10.1038/s41586-018-0436-0

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