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

Shunsuke Kimura, Petri Polonen, Lindsey Montefiori, Chun Shik Park, Ilaria Iacobucci, Allen Ej Yeoh, Andishe Attarbaschi, Andrew S Moore, Anthony Brown, Atsushi Manabe, Barbara Buldini, Burgess B Freeman, Chelsey Chen, Cheng Cheng, Chiew Kean Hui, Chi-Kong Li, Ching-Hon Pui, Chunxu Qu, Daisuke Tomizawa, David T TeacheyElena Varotto, Elisabeth M Paietta, Elizabeth D Arnold, Franco Locatelli, Gabriele Escherich, Hannah Elisa Muhle, Hanne Vibeke Marquart, Hester A de Groot-Kruseman, Jacob M Rowe, Jan Stary, Jan Trka, John Kim Choi, Jules P P Meijerink, Jun J Yang, Junko Takita, Katarzyna Pawinska-Wasikowska, Kathryn G Roberts, Katie Han, Kenneth J Caldwell, Kjeld Schmiegelow, Kristine R Crews, Mariko Eguchi, Martin Schrappe, Martin Zimmerman, Masatoshi Takagi, Mellissa Maybury, Michael Svaton, Michaela Reiterova, Michal Kicinski, Mollie S Prater, Motohiro Kato, Noemi Reyes, Orietta Spinelli, Paul Thomas, Pauline Mazilier, Qingsong Gao, Riccardo Masetti, Rishi S Kotecha, Rob Pieters, Sarah Elitzur, Selina M Luger, Sharnise Mitchell, Shondra M Pruett-Miller, Shuhong Shen, Sima Jeha, Stefan Köhrer, Steven M Kornblau, Szymon Skoczeń, Takako Miyamura, Tiffaney L Vincent, Toshihiko Imamura, Valentino Conter, Yanjing Tang, Yen-Chun Liu, Yunchao Chang, Zhaohui Gu, Zhongshan Cheng, Zhou Yinmei, Hiroto Inaba, Charles G Mullighan


PURPOSE: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease.

METHODS: We 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.

RESULTS: γδ 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 activating LMO2 activation and inactivating STAG2 inactivation ( 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.

CONCLUSION: γδ T-ALL in children under the age of three is extremely high-risk and enriched for STAG2/LMO2 ALL. STAG2 loss perturbs chromatin conformation and differentiation, and STAG2/LMO2 ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL.

SUPPORT: The 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.

DISCLAIMER: The 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.

StatusUdgivet - 8 nov. 2023
NavnmedRxiv : the preprint server for health sciences


Dyk ned i forskningsemnerne om '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'. Sammen danner de et unikt fingeraftryk.