Format

Send to

Choose Destination
Nat Genet. 2019 Feb;51(2):296-307. doi: 10.1038/s41588-018-0315-5. Epub 2019 Jan 14.

PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.

Author information

1
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
2
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
3
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
4
Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
5
Department of Transgenic/Gene Knockout Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, USA.
6
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
7
Department of Biostatistics, University of Florida, Gainesville, FL, USA.
8
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
9
Division of Pediatric Hematology-Oncology, New York University, New York, NY, USA.
10
Division of Hematologic Pathology, Johns Hopkins University, Baltimore, MD, USA.
11
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
12
Perlmutter Cancer Center, NYU-Langone Health, New York, NY, USA.
13
ImmunoGen, Inc, Waltham, MA, USA.
14
Baylor College of Medicine, Houston, TX, USA.
15
HARP Pharma Consulting, Mystic, CT, USA.
16
University of Colorado School of Medicine and Children's Hospital, Aurora, CO, USA.
17
Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
18
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
19
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
20
Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.
21
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
22
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
23
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
24
Cancer Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
25
Cytogenetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
26
Division of Hematology-Oncology, University of Birmingham, Birmingham, AL, USA.
27
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
28
University of Chicago Medical Center, Chicago, IL, USA.
29
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
30
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
31
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
32
Department of Pediatrics, UCSF Benioff Children's Hospital and the Helen Diller Family, San Francisco, CA, USA.
33
Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
34
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA. charles.mullighan@stjude.org.

Abstract

Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations); a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.

PMID:
30643249
PMCID:
PMC6525306
[Available on 2019-08-01]
DOI:
10.1038/s41588-018-0315-5
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center