Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk

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

doi:10.1158/2159-8290.CD-23-1452

Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk

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

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	1838-1859
Number of pages	22
Journal	Cancer Discovery
Volume	14
Issue number	10
DOIs	https://doi.org/10.1158/2159-8290.CD-23-1452
State	Published - 1 Oct 2024

Funding

Funders	Funder number
St Jude Children’s Research Hospital Comprehensive Cancer Center
St. Jude Children's Research Hospital
American and Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital
Univerzita Karlova v Praze	UNCE/24/MED/003
Ministerstvo Zdravotnictví Ceské Republiky	NU23J-03-00026
St. Baldrick's Foundation	R03CA256550, F32 5F32CA254140, X01HD100702
National Institutes of Health	U10CA180820, U24CA114766, U10CA180866, U10CA180899, UG1CA189859, U24CA196173
National Cancer Institute	P50 CA021765, R35 CA197695

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/2159-8290.CD-23-1452

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Kimura, S., Park, C. S., Montefiori, L. E., Iacobucci, I., Pölönen, P., Gao, Q., Arnold, E. D., Attarbaschi, A., Brown, A., Buldini, B., Caldwell, K. J., Chang, Y., Chen, C., Cheng, C., Cheng, Z., Choi, J., Conter, V., Crews, K. R., de Groot-Kruseman, H. A., ... Mullighan, C. G. (2024). Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk. Cancer Discovery, 14(10), 1838-1859. https://doi.org/10.1158/2159-8290.CD-23-1452

@article{b3b7d99ce51a483abe535c11c4c7737a,

title = "Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk",

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.",

author = "Shunsuke Kimura and Park, {Chun Shik} and Montefiori, {Lindsey E.} and Ilaria Iacobucci and Petri P{\"o}l{\"o}nen and Qingsong Gao and Arnold, {Elizabeth D.} and Andishe Attarbaschi and Anthony Brown and Barbara Buldini and Caldwell, {Kenneth J.} and Yunchao Chang and Chelsey Chen and Cheng Cheng and Zhongshan Cheng and John Choi and Valentino Conter and Crews, {Kristine R.} and {de Groot-Kruseman}, {Hester A.} and Takao Deguchi and Mariko Eguchi and Muhle, {Hannah E.} and Sarah Elitzur and Gabriele Escherich and Freeman, {Burgess B.} and Zhaohui Gu and Katie Han and Keizo Horibe and Toshihiko Imamura and Sima Jeha and Motohiro Kato and Chiew, {Kean H.} and Tanya Khan and Michal Kicinski and Stefan K{\"o}hrer and Kornblau, {Steven M.} and Kotecha, {Rishi S.} and Li, {Chi Kong} and Liu, {Yen Chun} and Franco Locatelli and Luger, {Selina M.} and Paietta, {Elisabeth M.} and Atsushi Manabe and Marquart, {Hanne V.} and Riccardo Masetti and Mellissa Maybury and Pauline Mazilier and Meijerink, {Jules P.P.} and Sharnise Mitchell and Takako Miyamura and Moore, {Andrew S.} and Koichi Oshima and Katarzyna Pawinska-Wasikowska and Rob Pieters and Prater, {Mollie S.} and Pruett-Miller, {Shondra M.} and Pui, {Ching Hon} and Chunxu Qu and Michaela Reiterova and Noemi Reyes and Roberts, {Kathryn G.} and Rowe, {Jacob M.} and Atsushi Sato and Kjeld Schmiegelow and Martin Schrappe and Shuhong Shen and Szymon Skocze{\'n} and Orietta Spinelli and Jan Stary and Michael Svaton and Masatoshi Takagi and Junko Takita and Yanjing Tang and Teachey, {David T.} and Thomas, {Paul G.} and Daisuke Tomizawa and Jan Trka and Elena Varotto and Vincent, {Tiffaney L.} and Yang, {Jun J.} and Yeoh, {Allen E.J.} and Yinmei Zhou and Martin Zimmermann and Hiroto Inaba and Mullighan, {Charles G.}",

note = "Publisher Copyright: {\textcopyright} 2024 American Association for Cancer Research.",

year = "2024",

month = oct,

day = "1",

doi = "10.1158/2159-8290.CD-23-1452",

language = "אנגלית",

volume = "14",

pages = "1838--1859",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "10",

}

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, 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 & Mullighan, CG 2024, 'Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk', Cancer Discovery, vol. 14, no. 10, pp. 1838-1859. https://doi.org/10.1158/2159-8290.CD-23-1452

TY - JOUR

T1 - Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk

AU - Kimura, Shunsuke

AU - Park, Chun Shik

AU - Montefiori, Lindsey E.

AU - Iacobucci, Ilaria

AU - Pölönen, Petri

AU - Gao, Qingsong

AU - Arnold, Elizabeth D.

AU - Attarbaschi, Andishe

AU - Brown, Anthony

AU - Buldini, Barbara

AU - Caldwell, Kenneth J.

AU - Chang, Yunchao

AU - Chen, Chelsey

AU - Cheng, Cheng

AU - Cheng, Zhongshan

AU - Choi, John

AU - Conter, Valentino

AU - Crews, Kristine R.

AU - de Groot-Kruseman, Hester A.

AU - Deguchi, Takao

AU - Eguchi, Mariko

AU - Muhle, Hannah E.

AU - Elitzur, Sarah

AU - Escherich, Gabriele

AU - Freeman, Burgess B.

AU - Gu, Zhaohui

AU - Han, Katie

AU - Horibe, Keizo

AU - Imamura, Toshihiko

AU - Jeha, Sima

AU - Kato, Motohiro

AU - Chiew, Kean H.

AU - Khan, Tanya

AU - Kicinski, Michal

AU - Köhrer, Stefan

AU - Kornblau, Steven M.

AU - Kotecha, Rishi S.

AU - Li, Chi Kong

AU - Liu, Yen Chun

AU - Locatelli, Franco

AU - Luger, Selina M.

AU - Paietta, Elisabeth M.

AU - Manabe, Atsushi

AU - Marquart, Hanne V.

AU - Masetti, Riccardo

AU - Maybury, Mellissa

AU - Mazilier, Pauline

AU - Meijerink, Jules P.P.

AU - Mitchell, Sharnise

AU - Miyamura, Takako

AU - Moore, Andrew S.

AU - Oshima, Koichi

AU - Pawinska-Wasikowska, Katarzyna

AU - Pieters, Rob

AU - Prater, Mollie S.

AU - Pruett-Miller, Shondra M.

AU - Pui, Ching Hon

AU - Qu, Chunxu

AU - Reiterova, Michaela

AU - Reyes, Noemi

AU - Roberts, Kathryn G.

AU - Rowe, Jacob M.

AU - Sato, Atsushi

AU - Schmiegelow, Kjeld

AU - Schrappe, Martin

AU - Shen, Shuhong

AU - Skoczeń, Szymon

AU - Spinelli, Orietta

AU - Stary, Jan

AU - Svaton, Michael

AU - Takagi, Masatoshi

AU - Takita, Junko

AU - Tang, Yanjing

AU - Teachey, David T.

AU - Thomas, Paul G.

AU - Tomizawa, Daisuke

AU - Trka, Jan

AU - Varotto, Elena

AU - Vincent, Tiffaney L.

AU - Yang, Jun J.

AU - Yeoh, Allen E.J.

AU - Zhou, Yinmei

AU - Zimmermann, Martin

AU - Inaba, Hiroto

AU - Mullighan, Charles G.

PY - 2024/10/1

Y1 - 2024/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85199691168&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-23-1452

DO - 10.1158/2159-8290.CD-23-1452

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 38916500

AN - SCOPUS:85199691168

SN - 2159-8274

VL - 14

SP - 1838

EP - 1859

JO - Cancer Discovery

JF - Cancer Discovery

IS - 10

ER -

Biologic and Clinical Analysis of Childhood Gamma Delta T-ALL Identifies LMO2/STAG2 Rearrangements as Extremely High Risk

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