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Nature. 2018 Oct;562(7727):373-379. doi: 10.1038/s41586-018-0436-0. Epub 2018 Sep 12.

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

Author information

1
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
2
Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA.
3
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
4
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
5
Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
6
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University School of Medicine, Department of Pediatrics, Atlanta, GA, USA.
7
Department of Women and Child Health, Hemato-Oncology Division, University of Padova, Padova, Italy.
8
Pediatric Hematology-Oncology, Schneider Children's Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel.
9
Prinses Maxima Centre, Utrecht, The Netherlands.
10
Department of Pediatric Oncology, Erasmus MC-Sophia, Rotterdam, The Netherlands.
11
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
12
Universit├Ąts-Klinikum, Essen, Germany.
13
Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
14
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
15
Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
16
The Tumour Bank CCRU, The Kids Research Institute, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
17
Department of Pediatrics, Mie University, Tsu, Japan.
18
Wolfson Childhood Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
19
The University of Queensland Diamantina Institute & Children's Health, Brisbane, Queensland, Australia.
20
Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
21
Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA.
22
Children's Oncology Group, Arcadia, CA, USA.
23
Children's Center for Cancer and Blood Disease, Children's Hospital Los Angeles, Los Angeles, CA, USA.
24
University of Florida, Gainesville, FL, USA.
25
Johns Hopkins Medical Institutions, Baltimore, MD, USA.
26
University of Washington, Seattle, WA, USA.
27
The Ohio State University School of Medicine, Columbus, OH, USA.
28
University of Alabama at Birmingham, Birmingham, AL, USA.
29
Department of Laboratory Medicine and Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
30
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.
31
Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, USA.
32
Office of Cancer Genomics, National Cancer Institute, Bethesda, MD, USA.
33
Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
34
Cytogenetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, USA.
35
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
36
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
37
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA. hiroto.inaba@stjude.org.
38
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA. charles.mullighan@stjude.org.

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.

PMID:
30209392
PMCID:
PMC6195459
[Available on 2019-04-01]
DOI:
10.1038/s41586-018-0436-0

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