Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young
Author:
Kimura ShunsukeORCID, Polonen Petri, Montefiori Lindsey, Park Chun Shik, Iacobucci Ilaria, Yeoh Allen EJ, Attarbaschi Andishe, Moore Andrew S., Brown Anthony, Manabe Atsushi, Buldini Barbara, Freeman Burgess B., Chen Chelsey, Cheng Cheng, Kean Hui Chiew, Li Chi-Kong, Pui Ching-Hon, Qu Chunxu, Tomizawa Daisuke, Teachey David T., Varotto Elena, Paietta Elisabeth M, Arnold Elizabeth D., Locatelli Franco, Escherich Gabriele, Elisa Muhle Hannah, Marquart Hanne Vibeke, de Groot-Kruseman Hester A., Rowe Jacob M., Stary Jan, Trka Jan, Choi John Kim, Meijerink Jules P.P., Yang Jun J., Takita Junko, Pawinska-Wasikowska Katarzyna, Roberts Kathryn G., Han Katie, Caldwell Kenneth J., Schmiegelow Kjeld, Crews Kristine R., Eguchi Mariko, Schrappe Martin, Zimmerman Martin, Takagi Masatoshi, Maybury Mellissa, Svaton Michael, Reiterova Michaela, Kicinski Michal, Prater Mollie S., Kato Motohiro, Reyes Noemi, Spinelli Orietta, Thomas Paul, Mazilier Pauline, Gao Qingsong, Masetti Riccardo, Kotecha Rishi S, Pieters Rob, Elitzur Sarah, Luger Selina M., Mitchell Sharnise, Pruett-Miller Shondra M., Shen Shuhong, Jeha Sima, Köhrer Stefan, Kornblau Steven M., Skoczeń Szymon, Miyamura Takako, Vincent Tiffaney L, Imamura Toshihiko, Conter Valentino, Tang Yanjing, Liu Yen-Chun, Chang Yunchao, Gu Zhaohui, Cheng Zhongshan, Yinmei Zhou, Inaba HirotoORCID, Mullighan Charles G.ORCID
Abstract
ABSTRACTPURPOSEGamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease.METHODSWe studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts.RESULTSγδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10],P=9.5 x 10-5) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10],P=0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activatingLMO2activation and inactivatingSTAG2inactivation (STAG2/LMO2). Mechanistically, 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. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine.CONCLUSIONγδ T-ALL in children under the age of three is extremely high-risk and enriched forSTAG2/LMO2ALL. STAG2 loss perturbs chromatin conformation and differentiation, andSTAG2/LMO2ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL.SUPPORTThe authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick’s Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children’s Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173.DISCLAIMERThe content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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