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Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk
S. Kimura, CS. Park, LE. Montefiori, I. Iacobucci, P. Pölönen, Q. Gao, ED. Arnold, A. Attarbaschi, A. Brown, B. Buldini, KJ. Caldwell, Y. Chang, C. Chen, C. Cheng, Z. Cheng, J. Choi, V. Conter, KR. Crews, HA. de Groot-Kruseman, T. Deguchi, M....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Grantová podpora
U10 CA180820
NCI NIH HHS - United States
T32 CA236748
NCI NIH HHS - United States
Henry Schueler 41&9 Foundation
UNCE/24/MED/003
Charles University Research Center
NU23J-03-00026
Ministry of Health of the Czech Republic
R35 CA197695
NCI NIH HHS - United States
F32 CA254140
NCI NIH HHS - United States
K99 CA279756
NCI NIH HHS - United States
X01 HD100702
Common Fund (NIH Common Fund)
Robert J. Arceci Innovation Award
St. Baldrick's Foundation (SBF)
- MeSH
- adaptorové proteiny signální transdukční * genetika metabolismus MeSH
- dítě MeSH
- genová přestavba MeSH
- kojenec MeSH
- lidé MeSH
- lymfoblastická leukemie-lymfom z prekurzorových T-buněk genetika patologie MeSH
- předškolní dítě MeSH
- proteiny buněčného cyklu genetika metabolismus MeSH
- proteiny s doménou LIM * genetika MeSH
- protoonkogenní proteiny MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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
Clinical Research Center National Hospital Organization Nagoya Medical Center Nagoya Japan
Curtin Medical School Curtin University Perth Australia
Department of Biostatistics St Jude Children's Research Hospital Memphis Tennessee
Department of Clinical Immunology Rigshospitalet Copenhagen Denmark
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 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 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 Medical School Hannover Hannover Germany
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 Systems Biology Beckman Research Institute of City of Hope Duarte California
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
Oncology Service Children's Health Queensland Hospital and Health Service Brisbane Australia
Pediatric Hemato Oncology and Transplantation HUB HUDERF Brussels Belgium
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
Citace poskytuje Crossref.org
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- $a X01 HD100702 $p Common Fund (NIH Common Fund)
- GRA __
- $a Robert J. Arceci Innovation Award $p St. Baldrick's Foundation (SBF)
- LZP __
- $a Pubmed-20250121
