The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

Yu Liu; John Easton; Ying Shao; Jamie Maciaszek; Zhaoming Wang; Mark R. Wilkinson; Kelly McCastlain; Michael Edmonson; Stanley B. Pounds; Lei Shi; Xin Zhou; Xiaotu Ma; Edgar Sioson; Yongjin Li; Michael Rusch; Pankaj Gupta; Deqing Pei; Cheng Cheng; Malcolm A. Smith; Jaime Guidry Auvil; Daniela S. Gerhard; Mary V. Relling; Naomi J. Winick; Andrew J. Carroll; Nyla A. Heerema; Elizabeth Raetz; Meenakshi Devidas; Cheryl L. Willman; Richard C. Harvey; William L. Carroll; Kimberly P. Dunsmore; Stuart S. Winter; Brent L. Wood; Brian P. Sorrentino; James R. Downing; Mignon L. Loh; Stephen P. Hunger; Jinghui Zhang; Charles G. Mullighan

doi:10.1038/ng.3909

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

Yu Liu, John Easton, Ying Shao, Jamie Maciaszek, Zhaoming Wang, Mark R. Wilkinson, Kelly McCastlain, Michael Edmonson, Stanley B. Pounds, Lei Shi, Xin Zhou, Xiaotu Ma, Edgar Sioson, Yongjin Li, Michael Rusch, Pankaj Gupta, Deqing Pei, Cheng Cheng, Malcolm A. Smith, Jaime Guidry AuvilDaniela S. Gerhard, Mary V. Relling, Naomi J. Winick, Andrew J. Carroll, Nyla A. Heerema, Elizabeth Raetz, Meenakshi Devidas, Cheryl L. Willman, Richard C. Harvey, William L. Carroll, Kimberly P. Dunsmore, Stuart S. Winter, Brent L. Wood, Brian P. Sorrentino, James R. Downing, Mignon L. Loh, Stephen P. Hunger, Jinghui Zhang, Charles G. Mullighan

Laboratory Medicine and Pathology

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

Abstract

Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.

Original language	English (US)
Pages (from-to)	1211-1218
Number of pages	8
Journal	Nature Genetics
Volume	49
Issue number	8
DOIs	https://doi.org/10.1038/ng.3909
State	Published - Aug 1 2017

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/ng.3909

Cite this

Liu, Y., Easton, J., Shao, Y., Maciaszek, J., Wang, Z., Wilkinson, M. R., McCastlain, K., Edmonson, M., Pounds, S. B., Shi, L., Zhou, X., Ma, X., Sioson, E., Li, Y., Rusch, M., Gupta, P., Pei, D., Cheng, C., Smith, M. A., ... Mullighan, C. G. (2017). The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nature Genetics, 49(8), 1211-1218. https://doi.org/10.1038/ng.3909

Liu, Y, Easton, J, Shao, Y, Maciaszek, J, Wang, Z, Wilkinson, MR, McCastlain, K, Edmonson, M, Pounds, SB, Shi, L, Zhou, X, Ma, X, Sioson, E, Li, Y, Rusch, M, Gupta, P, Pei, D, Cheng, C, Smith, MA, Auvil, JG, Gerhard, DS, Relling, MV, Winick, NJ, Carroll, AJ, Heerema, NA, Raetz, E, Devidas, M, Willman, CL, Harvey, RC, Carroll, WL, Dunsmore, KP, Winter, SS, Wood, BL, Sorrentino, BP, Downing, JR, Loh, ML, Hunger, SP, Zhang, J & Mullighan, CG 2017, 'The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia', Nature Genetics, vol. 49, no. 8, pp. 1211-1218. https://doi.org/10.1038/ng.3909

@article{4ba5662ce5ba4d4baa71fd1e4b185e97,

title = "The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia",

abstract = "Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.",

author = "Yu Liu and John Easton and Ying Shao and Jamie Maciaszek and Zhaoming Wang and Wilkinson, {Mark R.} and Kelly McCastlain and Michael Edmonson and Pounds, {Stanley B.} and Lei Shi and Xin Zhou and Xiaotu Ma and Edgar Sioson and Yongjin Li and Michael Rusch and Pankaj Gupta and Deqing Pei and Cheng Cheng and Smith, {Malcolm A.} and Auvil, {Jaime Guidry} and Gerhard, {Daniela S.} and Relling, {Mary V.} and Winick, {Naomi J.} and Carroll, {Andrew J.} and Heerema, {Nyla A.} and Elizabeth Raetz and Meenakshi Devidas and Willman, {Cheryl L.} and Harvey, {Richard C.} and Carroll, {William L.} and Dunsmore, {Kimberly P.} and Winter, {Stuart S.} and Wood, {Brent L.} and Sorrentino, {Brian P.} and Downing, {James R.} and Loh, {Mignon L.} and Hunger, {Stephen P.} and Jinghui Zhang and Mullighan, {Charles G.}",

year = "2017",

month = aug,

day = "1",

doi = "10.1038/ng.3909",

language = "English (US)",

volume = "49",

pages = "1211--1218",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "8",

}

TY - JOUR

T1 - The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

AU - Liu, Yu

AU - Easton, John

AU - Shao, Ying

AU - Maciaszek, Jamie

AU - Wang, Zhaoming

AU - Wilkinson, Mark R.

AU - McCastlain, Kelly

AU - Edmonson, Michael

AU - Pounds, Stanley B.

AU - Shi, Lei

AU - Zhou, Xin

AU - Ma, Xiaotu

AU - Sioson, Edgar

AU - Li, Yongjin

AU - Rusch, Michael

AU - Gupta, Pankaj

AU - Pei, Deqing

AU - Cheng, Cheng

AU - Smith, Malcolm A.

AU - Auvil, Jaime Guidry

AU - Gerhard, Daniela S.

AU - Relling, Mary V.

AU - Winick, Naomi J.

AU - Carroll, Andrew J.

AU - Heerema, Nyla A.

AU - Raetz, Elizabeth

AU - Devidas, Meenakshi

AU - Willman, Cheryl L.

AU - Harvey, Richard C.

AU - Carroll, William L.

AU - Dunsmore, Kimberly P.

AU - Winter, Stuart S.

AU - Wood, Brent L.

AU - Sorrentino, Brian P.

AU - Downing, James R.

AU - Loh, Mignon L.

AU - Hunger, Stephen P.

AU - Zhang, Jinghui

AU - Mullighan, Charles G.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.

AB - Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.

UR - http://www.scopus.com/inward/record.url?scp=85026366349&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026366349&partnerID=8YFLogxK

U2 - 10.1038/ng.3909

DO - 10.1038/ng.3909

M3 - Article

C2 - 28671688

AN - SCOPUS:85026366349

SN - 1061-4036

VL - 49

SP - 1211

EP - 1218

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this