Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High-throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by poly(ADP-ribose) polymerase inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric γδ T-ALL. Significance: Patients with acute lymphoblastic leukemia expressing the gamma delta T-cell receptor under 3 years old or measurable residual disease ≥1% at end of induction showed dismal outcomes and should be classified as having high-risk disease. The STAG2/LMO2 subtype was enriched in this very young age group. STAG2 inactivation may perturb chromatin conformation and cell differentiation and confer vulnerability to poly(ADP-ribose) polymerase inhibition.

Abramson Cancer Center Univeristy of Pennsylvania Philadelphia Pennsylvania

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria

Center for Applied Bioinformatics St Jude Children's Research Hospital Memphis Tennessee

Center of Excellence for Leukemia Studies St Jude Children's Research Hospital Memphis Tennessee

Child Health Research Centre the University of Queensland Brisbane Australia

Children's Cancer Center National Center for Child Health and Development Tokyo Japan

Clinic of Pediatric Hematology and Oncology University Medical Center Hamburg Eppendorf Hamburg Germany

Clinical Research Center National Hospital Organization Nagoya Medical Center Nagoya Japan

CLIP Childhood Leukaemia Investigation Prague Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czechia

Curtin Medical School Curtin University Perth Australia

Department of Biostatistics St Jude Children's Research Hospital Memphis Tennessee

Department of Cell and Molecular Biology and Center for Advance Genome Engineering St Jude Children's Research Hospital Memphis Tennessee

Department of Chemical Biology and Therapeutics St Jude Children's Research Hospital Memphis Tennessee

Department of Clinical Haematology Oncology Blood and Marrow Transplantation Perth Children's Hospital Perth Australia

Department of Clinical Immunology Rigshospitalet Copenhagen Denmark

Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Department of Computational and Quantitative Medicine Beckman Research Institute of City of Hope Duarte California

Department of Global Pediatric Medicine St Jude Children's Research Hospital Memphis Tennessee

Department of Hematology and Oncology Miyagi Children's Hospital Sendai Japan

Department of Hematology Oncology National Health Committee Key Laboratory of Pediatric Hematology and Oncology Shanghai Children's Medical Center Shanghai Jiao Tong University School of Medicine Shanghai China

Department of Hematology Oncology Saitama Children's Medical Center Saitama Japan

Department of Hematology Shaare Zedek Medical Center Jerusalem Israel

Department of Immunology St Jude Children's Research Hospital Memphis Tennessee

Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas

Department of Oncology Montefiore Medical Center Bronx New York

Department of Oncology St Jude Children's Research Hospital Memphis Tennessee

Department of Paediatrics National University of Singapore Singapore Singapore

Department of Paediatrics The Chinese University of Hong Kong Hong Kong China

Department of Paediatrics Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore

Department of Pathology St Jude Children's Research Hospital Memphis Tennessee

Department of Pathology University of Alabama at Birmingham Birmingham Alabama

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Pediatric Hematology and Oncology Medical School Hannover Hannover Germany

Department of Pediatric Hematology and Oncology Schneider Children's Medical Center and Faculty of Medicine Tel Aviv University Tel Aviv Israel

Department of Pediatric Hematology and Oncology St Anna Children's Hospital Medical University of Vienna Vienna Austria

Department of Pediatric Hematology Oncology and Cell and Gene Therapy IRCCS Ospedale Pediatrico Bambino Gesù Catholic University of the Sacred Heart Rome Italy

Department of Pediatric Oncology and Hematology Jagiellonian University Medical College Krakow Poland

Department of Pediatrics and Adolescent Medicine Rigshospitalet University Hospital København Denmark

Department of Pediatrics and Developmental Biology Tokyo Medical and Dental University Tokyo Japan

Department of Pediatrics Ehime University Matsuyama Japan

Department of Pediatrics Graduate School of Medicine Kyoto University Kyoto Japan

Department of Pediatrics Hokkaido University Graduate School of Medicine Sapporo Japan

Department of Pediatrics Kyoto Prefectural University of Medicine Tokyo Japan

Department of Pediatrics Osaka University Graduate School of Medicine Osaka Japan

Department of Pediatrics Tokyo University Tokyo Japan

Department of Pediatrics University Hospital Schleswig Holstein Kiel Germany

Department of Pharmacy and Pharmaceutical Sciences St Jude Children's Research Hospital Memphis Tennessee

Department of Systems Biology Beckman Research Institute of City of Hope Duarte California

Division of Leukemia and Lymphoma Children's Cancer Center National Center for Child Health and Development Tokyo Japan

Division of Oncology Children's Hospital of Philadelphia Philadelphia Pennsylvania

EORTC headquarters Brussels Belgium

Gilead Sciences Inc Foster City California

Hematology and Bone Marrow Transplant Unit ASST Papa Giovanni XXIII Hospital Bergamo Italy

Labdia Labordiagnostik GmbH Vienna Austria

Leukaemia Translational Research Laboratory Telethon Kids Cancer Centre Telethon Kids Institute University of Western Australia Perth Australia

Oncology Service Children's Health Queensland Hospital and Health Service Brisbane Australia

Pediatric Hemato Oncology and Transplantation HUB HUDERF Brussels Belgium

Pediatric Hematology and Oncology IRCCS Azienda Ospedaliero Universitaria di Bologna University of Bologna Bologna Italy

Pediatric Hematology Oncology and Stem Cell Transplant Division Maternal and Child Health Department University of Padova Padova Italy

Pediatric Onco Hematology Stem Cell Transplant and Gene Therapy Laboratory Istituto di Ricerca Pediatrica Città della Speranza Padova Italy

Preclinical Pharmacokinetic Shared Resource St Jude Children's Research Hospital Memphis Tennessee

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

St Anna Children's Cancer Research Institute Vienna Austria

Tettamanti Center Fondazione IRCCS San Gerardo dei Tintori Monza Italy

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