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Non-coding germline GATA3 variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia

Hongbo Yang, Hui Zhang, Yu Luan, Tingting Liu, Kathryn G Roberts, Mao-xiang Qian, Bo Zhang, Wenjian Yang, Virginia Perez-Andreu, Jie Xu, Sriranga Iyyanki, Da Kuang, Shalini C. Reshmi, Julie Gastier-Foster, Colton Smith, Ching-Hon Pui, William E Evans, Stephen P Hunger, Leonidas C. Platanias, Mary V Relling, View ORCID ProfileCharles G Mullighan, Mignon L Loh, Feng Yue, View ORCID ProfileJun J Yang
doi: https://doi.org/10.1101/2020.02.23.961672
Hongbo Yang
1Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, Illinois, USA
2Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
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Hui Zhang
3Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
4Department of Pediatric Hematology/Oncology, Guangzhou Women and Children’s Medical Center, Guangzhou, Guangdong, China
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Yu Luan
1Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, Illinois, USA
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Tingting Liu
1Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, Illinois, USA
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Kathryn G Roberts
5Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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Mao-xiang Qian
3Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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Bo Zhang
6Bioinformatics and Genomics Program, The Pennsylvania State University, University Park, Pennsylvania, USA
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Wenjian Yang
3Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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Virginia Perez-Andreu
3Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
7Internal Medicine Department, MountainView Hospital, University of Reno, Las Vegas, Nevada, USA
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Jie Xu
8Department of Biochemistry and Molecular Biology, Penn State School of Medicine, Hershey, Pennsylvania, USA
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Sriranga Iyyanki
8Department of Biochemistry and Molecular Biology, Penn State School of Medicine, Hershey, Pennsylvania, USA
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Da Kuang
9Department of Computer and Information Science, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Shalini C. Reshmi
10Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio, USA
11Department of Pediatrics, Ohio State University School of Medicine, Columbus, Ohio, USA
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Julie Gastier-Foster
10Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, Ohio, USA
11Department of Pediatrics, Ohio State University School of Medicine, Columbus, Ohio, USA
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Colton Smith
3Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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Ching-Hon Pui
12Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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William E Evans
3Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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Stephen P Hunger
13Division of Oncology and the Center for Childhood Cancer Research, Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Leonidas C. Platanias
2Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
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Mary V Relling
3Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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Charles G Mullighan
5Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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  • ORCID record for Charles G Mullighan
Mignon L Loh
14Department of Pediatrics, Benioff Children’s Hospital and the Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA
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Feng Yue
1Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine Northwestern University, Chicago, Illinois, USA
2Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
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  • For correspondence: jun.yang@stjude.org yue@northwesten.edu
Jun J Yang
3Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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  • ORCID record for Jun J Yang
  • For correspondence: jun.yang@stjude.org yue@northwesten.edu
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Abstract

Inherited non-coding genetic variants confer significant disease susceptibility in many cancers. However, the molecular processes of by which germline variants contribute to somatic lesions are poorly understood. We performed targeted sequencing in 5,008 patients and identified a key regulatory germline variant in GATA3 strongly associated with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). By creating an isogenic cellular model with CRISPR-Cas9 system, we showed that this variant activated a strong enhancer that significantly upregulated GATA3 transcription, which in turn reshaped the global chromatin accessibility and 3D genome organization. Remarkably, this genotype switch induced a chromatin loop between the CRLF2 oncogene and a distal enhancer, similar to the somatically acquired super-enhancer hijacking event in patients. GATA3 genotype-related alterations in transcriptional control and 3D chromatin organization were further validated in Ph-like ALL patients. Finally, we showed that GATA3 directly regulates CRLF2 and potentiates the oncogenic effects of JAK-STAT signaling in leukemogenesis. Altogether, our results provide evidence for a novel mechanism by which a germline non-coding variant contributes to oncogene activation epigenetic regulation and 3D genome reprogramming.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted February 25, 2020.
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Non-coding germline GATA3 variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia
Hongbo Yang, Hui Zhang, Yu Luan, Tingting Liu, Kathryn G Roberts, Mao-xiang Qian, Bo Zhang, Wenjian Yang, Virginia Perez-Andreu, Jie Xu, Sriranga Iyyanki, Da Kuang, 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
bioRxiv 2020.02.23.961672; doi: https://doi.org/10.1101/2020.02.23.961672
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Non-coding germline GATA3 variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia
Hongbo Yang, Hui Zhang, Yu Luan, Tingting Liu, Kathryn G Roberts, Mao-xiang Qian, Bo Zhang, Wenjian Yang, Virginia Perez-Andreu, Jie Xu, Sriranga Iyyanki, Da Kuang, 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
bioRxiv 2020.02.23.961672; doi: https://doi.org/10.1101/2020.02.23.961672

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