Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation

Hongbo Yang; Hui Zhang; Yu Luan; Tingting Liu; Wentao Yang; Kathryn G. Roberts; Mao xiang Qian; Bo Zhang; Wenjian Yang; Virginia Perez-Andreu; Jie Xu; Sriranga Iyyanki; Da Kuang; Lena A. Stasiak; Shalini C. Reshmi; Julie Gastier-Foster; Colton Smith; Ching Hon Pui; William E. Evans; Stephen P. Hunger; Leonidas C. Platanias; Mary V. Relling; Charles G. Mullighan; Mignon L. Loh; Feng Yue; Jun J. Yang

doi:10.1038/s41588-021-00993-x

Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation

Hongbo Yang, Hui Zhang, Yu Luan, Tingting Liu, Wentao Yang, Kathryn G. Roberts, Mao xiang Qian, Bo Zhang, Wenjian Yang, Virginia Perez-Andreu, Jie Xu, Sriranga Iyyanki, Da Kuang, Lena A. Stasiak, Shalini C. Reshmi, Julie Gastier-Foster, Colton Smith, Ching Hon Pui, William E. Evans, Stephen P. HungerLeonidas C. Platanias, Mary V. Relling, Charles G. Mullighan, Mignon L. Loh, Feng Yue, Jun J. Yang

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Abstract

Inherited noncoding genetic variants confer significant disease susceptibility to childhood acute lymphoblastic leukemia (ALL) but the molecular processes linking germline polymorphisms with somatic lesions in this cancer are poorly understood. Through targeted sequencing in 5,008 patients, we identified a key regulatory germline variant in GATA3 associated with Philadelphia chromosome-like ALL (Ph-like ALL). Using CRISPR–Cas9 editing and samples from patients with Ph-like ALL, we showed that this variant activated a strong enhancer that upregulated GATA3 transcription. This, in turn, reshaped global chromatin accessibility and three-dimensional genome organization, including regions proximal to the ALL oncogene CRLF2. Finally, we showed that GATA3 directly regulated CRLF2 and potentiated the JAK–STAT oncogenic effects during leukemogenesis. Taken together, we provide evidence for a distinct mechanism by which a germline noncoding variant contributes to oncogene activation, epigenetic regulation and three-dimensional genome reprogramming.

Original language	English
Pages (from-to)	170-179
Number of pages	10
Journal	Nature Genetics
Volume	54
Issue number	2
DOIs	https://doi.org/10.1038/s41588-021-00993-x
State	Published - Feb 2022
Externally published	Yes

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Yang, H., Zhang, H., Luan, Y., Liu, T., Yang, W., Roberts, K. G., Qian, M. X., Zhang, B., Yang, W., Perez-Andreu, V., Xu, J., Iyyanki, S., Kuang, D., Stasiak, L. A., Reshmi, S. C., Gastier-Foster, J., Smith, C., Pui, C. H., Evans, W. E., ... Yang, J. J. (2022). Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation. Nature Genetics, 54(2), 170-179. https://doi.org/10.1038/s41588-021-00993-x

@article{2eb2f390681948fb84014d719608df3c,

title = "Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation",

abstract = "Inherited noncoding genetic variants confer significant disease susceptibility to childhood acute lymphoblastic leukemia (ALL) but the molecular processes linking germline polymorphisms with somatic lesions in this cancer are poorly understood. Through targeted sequencing in 5,008 patients, we identified a key regulatory germline variant in GATA3 associated with Philadelphia chromosome-like ALL (Ph-like ALL). Using CRISPR–Cas9 editing and samples from patients with Ph-like ALL, we showed that this variant activated a strong enhancer that upregulated GATA3 transcription. This, in turn, reshaped global chromatin accessibility and three-dimensional genome organization, including regions proximal to the ALL oncogene CRLF2. Finally, we showed that GATA3 directly regulated CRLF2 and potentiated the JAK–STAT oncogenic effects during leukemogenesis. Taken together, we provide evidence for a distinct mechanism by which a germline noncoding variant contributes to oncogene activation, epigenetic regulation and three-dimensional genome reprogramming.",

author = "Hongbo Yang and Hui Zhang and Yu Luan and Tingting Liu and Wentao Yang and Roberts, {Kathryn G.} and Qian, {Mao xiang} and Bo Zhang and Wenjian Yang and Virginia Perez-Andreu and Jie Xu and Sriranga Iyyanki and Da Kuang and Stasiak, {Lena A.} and Reshmi, {Shalini C.} and Julie Gastier-Foster and Colton Smith and Pui, {Ching Hon} and Evans, {William E.} and Hunger, {Stephen P.} and Platanias, {Leonidas C.} and Relling, {Mary V.} and Mullighan, {Charles G.} and Loh, {Mignon L.} and Feng Yue and Yang, {Jun J.}",

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

year = "2022",

month = feb,

doi = "10.1038/s41588-021-00993-x",

language = "English",

volume = "54",

pages = "170--179",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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Yang, H, Zhang, H, Luan, Y, Liu, T, Yang, W, Roberts, KG, Qian, MX, Zhang, B, Yang, W, Perez-Andreu, V, Xu, J, Iyyanki, S, Kuang, D, Stasiak, LA, Reshmi, SC, Gastier-Foster, J, Smith, C, Pui, CH, Evans, WE, Hunger, SP, Platanias, LC, Relling, MV, Mullighan, CG, Loh, ML, Yue, F & Yang, JJ 2022, 'Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation', Nature Genetics, vol. 54, no. 2, pp. 170-179. https://doi.org/10.1038/s41588-021-00993-x

TY - JOUR

T1 - Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation

AU - Yang, Hongbo

AU - Zhang, Hui

AU - Luan, Yu

AU - Liu, Tingting

AU - Yang, Wentao

AU - Roberts, Kathryn G.

AU - Qian, Mao xiang

AU - Zhang, Bo

AU - Yang, Wenjian

AU - Perez-Andreu, Virginia

AU - Xu, Jie

AU - Iyyanki, Sriranga

AU - Kuang, Da

AU - Stasiak, Lena A.

AU - Reshmi, Shalini C.

AU - Gastier-Foster, Julie

AU - Smith, Colton

AU - Pui, Ching Hon

AU - Evans, William E.

AU - Hunger, Stephen P.

AU - Platanias, Leonidas C.

AU - Relling, Mary V.

AU - Mullighan, Charles G.

AU - Loh, Mignon L.

AU - Yue, Feng

AU - Yang, Jun J.

PY - 2022/2

Y1 - 2022/2

N2 - Inherited noncoding genetic variants confer significant disease susceptibility to childhood acute lymphoblastic leukemia (ALL) but the molecular processes linking germline polymorphisms with somatic lesions in this cancer are poorly understood. Through targeted sequencing in 5,008 patients, we identified a key regulatory germline variant in GATA3 associated with Philadelphia chromosome-like ALL (Ph-like ALL). Using CRISPR–Cas9 editing and samples from patients with Ph-like ALL, we showed that this variant activated a strong enhancer that upregulated GATA3 transcription. This, in turn, reshaped global chromatin accessibility and three-dimensional genome organization, including regions proximal to the ALL oncogene CRLF2. Finally, we showed that GATA3 directly regulated CRLF2 and potentiated the JAK–STAT oncogenic effects during leukemogenesis. Taken together, we provide evidence for a distinct mechanism by which a germline noncoding variant contributes to oncogene activation, epigenetic regulation and three-dimensional genome reprogramming.

AB - Inherited noncoding genetic variants confer significant disease susceptibility to childhood acute lymphoblastic leukemia (ALL) but the molecular processes linking germline polymorphisms with somatic lesions in this cancer are poorly understood. Through targeted sequencing in 5,008 patients, we identified a key regulatory germline variant in GATA3 associated with Philadelphia chromosome-like ALL (Ph-like ALL). Using CRISPR–Cas9 editing and samples from patients with Ph-like ALL, we showed that this variant activated a strong enhancer that upregulated GATA3 transcription. This, in turn, reshaped global chromatin accessibility and three-dimensional genome organization, including regions proximal to the ALL oncogene CRLF2. Finally, we showed that GATA3 directly regulated CRLF2 and potentiated the JAK–STAT oncogenic effects during leukemogenesis. Taken together, we provide evidence for a distinct mechanism by which a germline noncoding variant contributes to oncogene activation, epigenetic regulation and three-dimensional genome reprogramming.

UR - http://www.scopus.com/inward/record.url?scp=85124129506&partnerID=8YFLogxK

U2 - 10.1038/s41588-021-00993-x

DO - 10.1038/s41588-021-00993-x

M3 - Article

C2 - 35115686

AN - SCOPUS:85124129506

SN - 1061-4036

VL - 54

SP - 170

EP - 179

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation

Abstract

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