1Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA. 2Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA. 3Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA. 4Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. 5Department of Transgenic/Gene Knockout Shared Resource, St. Jude Children’s Research Hospital, Memphis, TN, USA. 6Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA. 7Department of Biostatistics, University of Florida, Gainesville, FL, USA. 8Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA. 9Division of Pediatric HematologyOncology, New York University, New York, NY, USA. 10Division of Hematologic Pathology, Johns Hopkins University, Baltimore, MD, USA. 11Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. 12Perlmutter Cancer Center, NYU-Langone Health, New York, NY, USA. 13ImmunoGen, Inc, Waltham, MA, USA. 14Baylor College of Medicine, Houston, TX, USA. 15HARP Pharma Consulting, Mystic, CT, USA. 16University of Colorado School of Medicine and Children’s Hospital, Aurora,, CO, USA. 17Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy. 18Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 19Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. 20Hematology, Shaare Zedek Medical Center, Jerusalem, Israel. 21Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. 22Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA. 23Memorial Sloan Kettering Cancer Center, New York, NY, USA. 24Cancer Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA. 25Cytogenetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 26Division of Hematology-Oncology, University of Birmingham, Birmingham, AL, USA. 27Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. 28University of Chicago Medical Center, Chicago, IL, USA. 29Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 30Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA. 31Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA. 32Department of Pediatrics, UCSF Benioff Children’s Hospital and the Helen Diller Family, San Francisco, CA, USA. 33Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. 34These authors contributed equally: Z. Gu, M. L. Churchman, K. G. Roberts. *e-mail: charles.mullighan@stjude.org B-progenitor acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy1, and it consists of multiple subtypes with distinct constellations of inherited and somatic genetic alterations2. Genomic analyses, especially transcriptome sequencing (RNA-seq), have identified recurrent chromosomal rearrangements that lead to expression of chimeric fusion transcripts that define new subtypes of ALL3–12. In contrast to subtypes characterized by aneuploidy or a single chromosomal rearrangement resulting in expression of chimeric fusion oncoproteins (for example, ETV6-RUNX1, BCR-ABL1 or TCF3-PBX1), rearrangements PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia