Data from Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies <i>LMO2/STAG2</i> Rearrangements as Extremely High Risk
Authors: Kimura Shunsuke , Park Chun Shik , Montefiori Lindsey E. , Iacobucci Ilaria , Pölönen Petri , Gao Qingsong , Arnold Elizabeth D. , Attarbaschi Andishe , Brown Anthony , Buldini Barbara , Caldwell Kenneth J. , Chang Yunchao , Chen Chelsey , Cheng Cheng , Cheng Zhongshan , Choi John , Conter Valentino , Crews Kristine R. , de Groot-Kruseman Hester A. , Deguchi Takao , Eguchi Mariko , Muhle Hannah E. , Elitzur Sarah , Escherich Gabriele , Freeman Burgess B. , Gu Zhaohui , Han Katie , Horibe Keizo , Imamura Toshihiko , Jeha Sima , Kato Motohiro , Chiew Kean H. , Khan Tanya , Kicinski Michal , Köhrer Stefan , Kornblau Steven M. , Kotecha Rishi S. , Li Chi-Kong , Liu Yen-Chun , Locatelli Franco , Luger Selina M. , Paietta Elisabeth M. , Manabe Atsushi , Marquart Hanne V. , Masetti Riccardo , Maybury Mellissa , Mazilier Pauline , Meijerink Jules P.P. , Mitchell Sharnise , Miyamura Takako , Moore Andrew S. , Oshima Koichi , Pawinska-Wasikowska Katarzyna , Pieters Rob , Prater Mollie S. , Pruett-Miller Shondra M. , Pui Ching-Hon , Qu Chunxu , Reiterova Michaela , Reyes Noemi , Roberts Kathryn G. , Rowe Jacob M. , Sato Atsushi , Schmiegelow Kjeld , Schrappe Martin , Shen Shuhong , Skoczeń Szymon , Spinelli Orietta , Stary Jan , Svaton Michael , Takagi Masatoshi , Takita Junko , Tang Yanjing , Teachey David T. , Thomas Paul G. , Tomizawa Daisuke , Trka Jan , Varotto Elena , Vincent Tiffaney L. , Yang Jun J. , Yeoh Allen E.J. , Zhou Yinmei , Zimmermann Martin , Inaba Hiroto , Mullighan Charles G. 
Published: October 2024

<div>Abstract<p>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 <i>LMO2</i> activation and <i>STAG2</i> 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.</p><p><b>Significance:</b> 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.</p></div>