The genomic landscape of pediatric acute lymphoblastic leukemia

Samuel W. Brady; Kathryn G. Roberts; Zhaohui Gu; Lei Shi; Stanley Pounds; Deqing Pei; Cheng Cheng; Yunfeng Dai; Meenakshi Devidas; Chunxu Qu; Ashley N. Hill; Debbie Payne-Turner; Xiaotu Ma; Ilaria Iacobucci; Pradyuamna Baviskar; Lei Wei; Sasi Arunachalam; Kohei Hagiwara; Yanling Liu; Diane A. Flasch; Yu Liu; Matthew Parker; Xiaolong Chen; Abdelrahman H. Elsayed; Omkar Pathak; Yongjin Li; Yiping Fan; J. Robert Michael; Michael Rusch; Mark R. Wilkinson; Scott Foy; Dale J. Hedges; Scott Newman; Xin Zhou; Jian Wang; Colleen Reilly; Edgar Sioson; Stephen V. Rice; Victor Pastor Loyola; Gang Wu; Evadnie Rampersaud; Shalini C. Reshmi; Julie Gastier-Foster; Jaime M. Guidry Auvil; Patee Gesuwan; Malcolm A. Smith; Naomi Winick; Andrew J. Carroll; Nyla A. Heerema; Richard C. Harvey; Cheryl L. Willman; Eric Larsen; Elizabeth A. Raetz; Michael J. Borowitz; Brent L. Wood; William L. Carroll; Patrick A. Zweidler-McKay; Karen R. Rabin; Leonard A. Mattano; Kelly W. Maloney; Stuart S. Winter; Michael J. Burke; Wanda Salzer; Kimberly P. Dunsmore; Anne L. Angiolillo; Kristine R. Crews; James R. Downing; Sima Jeha; Ching Hon Pui; William E. Evans; Jun J. Yang; Mary V. Relling; Daniela S. Gerhard; Mignon L. Loh; Stephen P. Hunger; Jinghui Zhang; Charles G. Mullighan

doi:10.1038/s41588-022-01159-z

The genomic landscape of pediatric acute lymphoblastic leukemia

Samuel W. Brady, Kathryn G. Roberts, Zhaohui Gu, Lei Shi, Stanley Pounds, Deqing Pei, Cheng Cheng, Yunfeng Dai, Meenakshi Devidas, Chunxu Qu, Ashley N. Hill, Debbie Payne-Turner, Xiaotu Ma, Ilaria Iacobucci, Pradyuamna Baviskar, Lei Wei, Sasi Arunachalam, Kohei Hagiwara, Yanling Liu, Diane A. FlaschYu Liu, Matthew Parker, Xiaolong Chen, Abdelrahman H. Elsayed, Omkar Pathak, Yongjin Li, Yiping Fan, J. Robert Michael, Michael Rusch, Mark R. Wilkinson, Scott Foy, Dale J. Hedges, Scott Newman, Xin Zhou, Jian Wang, Colleen Reilly, Edgar Sioson, Stephen V. Rice, Victor Pastor Loyola, Gang Wu, Evadnie Rampersaud, Shalini C. Reshmi, Julie Gastier-Foster, Jaime M. Guidry Auvil, Patee Gesuwan, Malcolm A. Smith, Naomi Winick, Andrew J. Carroll, Nyla A. Heerema, Richard C. Harvey, Cheryl L. Willman, Eric Larsen, Elizabeth A. Raetz, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Patrick A. Zweidler-McKay, Karen R. Rabin, Leonard A. Mattano, Kelly W. Maloney, Stuart S. Winter, Michael J. Burke, Wanda Salzer, Kimberly P. Dunsmore, Anne L. Angiolillo, Kristine R. Crews, James R. Downing, Sima Jeha, Ching Hon Pui, William E. Evans, Jun J. Yang, Mary V. Relling, Daniela S. Gerhard, Mignon L. Loh, Stephen P. Hunger, Jinghui Zhang, Charles G. Mullighan

Laboratory Medicine and Pathology

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

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.

Original language	English (US)
Pages (from-to)	1376-1389
Number of pages	14
Journal	Nature Genetics
Volume	54
Issue number	9
DOIs	https://doi.org/10.1038/s41588-022-01159-z
State	Published - Sep 2022

ASJC Scopus subject areas

Genetics

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Brady, S. W., Roberts, K. G., Gu, Z., Shi, L., Pounds, S., Pei, D., Cheng, C., Dai, Y., Devidas, M., Qu, C., Hill, A. N., Payne-Turner, D., Ma, X., Iacobucci, I., Baviskar, P., Wei, L., Arunachalam, S., Hagiwara, K., Liu, Y., ... Mullighan, C. G. (2022). The genomic landscape of pediatric acute lymphoblastic leukemia. Nature Genetics, 54(9), 1376-1389. https://doi.org/10.1038/s41588-022-01159-z

Brady, SW, Roberts, KG, Gu, Z, Shi, L, Pounds, S, Pei, D, Cheng, C, Dai, Y, Devidas, M, Qu, C, Hill, AN, Payne-Turner, D, Ma, X, Iacobucci, I, Baviskar, P, Wei, L, Arunachalam, S, Hagiwara, K, Liu, Y, Flasch, DA, Liu, Y, Parker, M, Chen, X, Elsayed, AH, Pathak, O, Li, Y, Fan, Y, Michael, JR, Rusch, M, Wilkinson, MR, Foy, S, Hedges, DJ, Newman, S, Zhou, X, Wang, J, Reilly, C, Sioson, E, Rice, SV, Pastor Loyola, V, Wu, G, Rampersaud, E, Reshmi, SC, Gastier-Foster, J, Guidry Auvil, JM, Gesuwan, P, Smith, MA, Winick, N, Carroll, AJ, Heerema, NA, Harvey, RC, Willman, CL, Larsen, E, Raetz, EA, Borowitz, MJ, Wood, BL, Carroll, WL, Zweidler-McKay, PA, Rabin, KR, Mattano, LA, Maloney, KW, Winter, SS, Burke, MJ, Salzer, W, Dunsmore, KP, Angiolillo, AL, Crews, KR, Downing, JR, Jeha, S, Pui, CH, Evans, WE, Yang, JJ, Relling, MV, Gerhard, DS, Loh, ML, Hunger, SP, Zhang, J & Mullighan, CG 2022, 'The genomic landscape of pediatric acute lymphoblastic leukemia', Nature Genetics, vol. 54, no. 9, pp. 1376-1389. https://doi.org/10.1038/s41588-022-01159-z

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title = "The genomic landscape of pediatric acute lymphoblastic leukemia",

abstract = "Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.",

author = "Brady, {Samuel W.} and Roberts, {Kathryn G.} and Zhaohui Gu and Lei Shi and Stanley Pounds and Deqing Pei and Cheng Cheng and Yunfeng Dai and Meenakshi Devidas and Chunxu Qu and Hill, {Ashley N.} and Debbie Payne-Turner and Xiaotu Ma and Ilaria Iacobucci and Pradyuamna Baviskar and Lei Wei and Sasi Arunachalam and Kohei Hagiwara and Yanling Liu and Flasch, {Diane A.} and Yu Liu and Matthew Parker and Xiaolong Chen and Elsayed, {Abdelrahman H.} and Omkar Pathak and Yongjin Li and Yiping Fan and Michael, {J. Robert} and Michael Rusch and Wilkinson, {Mark R.} and Scott Foy and Hedges, {Dale J.} and Scott Newman and Xin Zhou and Jian Wang and Colleen Reilly and Edgar Sioson and Rice, {Stephen V.} and {Pastor Loyola}, Victor and Gang Wu and Evadnie Rampersaud and Reshmi, {Shalini C.} and Julie Gastier-Foster and {Guidry Auvil}, {Jaime M.} and Patee Gesuwan and Smith, {Malcolm A.} and Naomi Winick and Carroll, {Andrew J.} and Heerema, {Nyla A.} and Harvey, {Richard C.} and Willman, {Cheryl L.} and Eric Larsen and Raetz, {Elizabeth A.} and Borowitz, {Michael J.} and Wood, {Brent L.} and Carroll, {William L.} and Zweidler-McKay, {Patrick A.} and Rabin, {Karen R.} and Mattano, {Leonard A.} and Maloney, {Kelly W.} and Winter, {Stuart S.} and Burke, {Michael J.} and Wanda Salzer and Dunsmore, {Kimberly P.} and Angiolillo, {Anne L.} and Crews, {Kristine R.} and Downing, {James R.} and Sima Jeha and Pui, {Ching Hon} and Evans, {William E.} and Yang, {Jun J.} and Relling, {Mary V.} and Gerhard, {Daniela S.} and Loh, {Mignon L.} and Hunger, {Stephen P.} and Jinghui Zhang and Mullighan, {Charles G.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = sep,

doi = "10.1038/s41588-022-01159-z",

language = "English (US)",

volume = "54",

pages = "1376--1389",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

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T1 - The genomic landscape of pediatric acute lymphoblastic leukemia

AU - Brady, Samuel W.

AU - Roberts, Kathryn G.

AU - Gu, Zhaohui

AU - Shi, Lei

AU - Pounds, Stanley

AU - Pei, Deqing

AU - Cheng, Cheng

AU - Dai, Yunfeng

AU - Devidas, Meenakshi

AU - Qu, Chunxu

AU - Hill, Ashley N.

AU - Payne-Turner, Debbie

AU - Ma, Xiaotu

AU - Iacobucci, Ilaria

AU - Baviskar, Pradyuamna

AU - Wei, Lei

AU - Arunachalam, Sasi

AU - Hagiwara, Kohei

AU - Liu, Yanling

AU - Flasch, Diane A.

AU - Liu, Yu

AU - Parker, Matthew

AU - Chen, Xiaolong

AU - Elsayed, Abdelrahman H.

AU - Pathak, Omkar

AU - Li, Yongjin

AU - Fan, Yiping

AU - Michael, J. Robert

AU - Rusch, Michael

AU - Wilkinson, Mark R.

AU - Foy, Scott

AU - Hedges, Dale J.

AU - Newman, Scott

AU - Zhou, Xin

AU - Wang, Jian

AU - Reilly, Colleen

AU - Sioson, Edgar

AU - Rice, Stephen V.

AU - Pastor Loyola, Victor

AU - Wu, Gang

AU - Rampersaud, Evadnie

AU - Reshmi, Shalini C.

AU - Gastier-Foster, Julie

AU - Guidry Auvil, Jaime M.

AU - Gesuwan, Patee

AU - Smith, Malcolm A.

AU - Winick, Naomi

AU - Carroll, Andrew J.

AU - Heerema, Nyla A.

AU - Harvey, Richard C.

AU - Willman, Cheryl L.

AU - Larsen, Eric

AU - Raetz, Elizabeth A.

AU - Borowitz, Michael J.

AU - Wood, Brent L.

AU - Carroll, William L.

AU - Zweidler-McKay, Patrick A.

AU - Rabin, Karen R.

AU - Mattano, Leonard A.

AU - Maloney, Kelly W.

AU - Winter, Stuart S.

AU - Burke, Michael J.

AU - Salzer, Wanda

AU - Dunsmore, Kimberly P.

AU - Angiolillo, Anne L.

AU - Crews, Kristine R.

AU - Downing, James R.

AU - Jeha, Sima

AU - Pui, Ching Hon

AU - Evans, William E.

AU - Yang, Jun J.

AU - Relling, Mary V.

AU - Gerhard, Daniela S.

AU - Loh, Mignon L.

AU - Hunger, Stephen P.

AU - Zhang, Jinghui

AU - Mullighan, Charles G.

PY - 2022/9

Y1 - 2022/9

N2 - Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.

AB - Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.

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JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

The genomic landscape of pediatric acute lymphoblastic leukemia

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