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

Author

Listed:
  • Thomas B. Alexander

    (St. Jude Children’s Research Hospital
    University of North Carolina)

  • 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
    Erasmus MC-Sophia)

  • 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
    Children’s Oncology Group)

  • 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)

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.

Suggested Citation

  • 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 Bas, 2018. "The genetic basis and cell of origin of mixed phenotype acute leukaemia," Nature, Nature, vol. 562(7727), pages 373-379, October.
    • Handle: RePEc:nat:nature:v:562:y:2018:i:7727:d:10.1038_s41586-018-0436-0
    DOI: 10.1038/s41586-018-0436-0
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    Citations

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    Cited by:

    1. Cheryl A. C. Peretz & Vanessa E. Kennedy & Anushka Walia & Cyrille L. Delley & Andrew Koh & Elaine Tran & Iain C. Clark & Corey E. Hayford & Chris D’Amato & Yi Xue & Kristina M. Fontanez & Aaron A. Ma, 2024. "Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Xujie Zhao & Ping Wang & Jonathan D. Diedrich & Brandon Smart & Noemi Reyes & Satoshi Yoshimura & Jingliao Zhang & Wentao Yang & Kelly Barnett & Beisi Xu & Zhenhua Li & Xin Huang & Jiyang Yu & Kristin, 2022. "Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Roger Mulet-Lazaro & Stanley Herk & Margit Nuetzel & Aniko Sijs-Szabo & Noelia Díaz & Katherine Kelly & Claudia Erpelinck-Verschueren & Lucia Schwarzfischer-Pfeilschifter & Hanna Stanewsky & Ute Acker, 2024. "Epigenetic alterations affecting hematopoietic regulatory networks as drivers of mixed myeloid/lymphoid leukemia," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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