1. Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk.
- Author
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Kimura S, Park CS, Montefiori LE, Iacobucci I, Pölönen P, Gao Q, Arnold ED, Attarbaschi A, Brown A, Buldini B, Caldwell KJ, Chang Y, Chen C, Cheng C, Cheng Z, Choi J, Conter V, Crews KR, de Groot-Kruseman HA, Deguchi T, Eguchi M, Muhle HE, Elitzur S, Escherich G, Freeman BB 3rd, Gu Z, Han K, Horibe K, Imamura T, Jeha S, Kato M, Chiew KH, Khan T, Kicinski M, Köhrer S, Kornblau SM, Kotecha RS, Li CK, Liu YC, Locatelli F, Luger SM, Paietta EM, Manabe A, Marquart HV, Masetti R, Maybury M, Mazilier P, Meijerink JPP, Mitchell S, Miyamura T, Moore AS, Oshima K, Pawinska-Wasikowska K, Pieters R, Prater MS, Pruett-Miller SM, Pui CH, Qu C, Reiterova M, Reyes N, Roberts KG, Rowe JM, Sato A, Schmiegelow K, Schrappe M, Shen S, Skoczeń S, Spinelli O, Stary J, Svaton M, Takagi M, Takita J, Tang Y, Teachey DT, Thomas PG, Tomizawa D, Trka J, Varotto E, Vincent TL, Yang JJ, Yeoh AEJ, Zhou Y, Zimmermann M, Inaba H, and Mullighan CG
- Subjects
- Humans, Child, Preschool, Male, Female, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Infant, Child, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Gene Rearrangement, Proto-Oncogene Proteins, LIM Domain Proteins genetics, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism
- Abstract
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., (©2024 American Association for Cancer Research.)
- Published
- 2024
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