3D genome alterations associated with dysregulated HOXA13 expression in high-risk T-lineage acute lymphoblastic leukemia

Lu Yang, Fengling Chen, Haichuan Zhu, Yang Chen, Bingjie Dong, Minglei Shi, Weitao Wang, Qian Jiang, Leping Zhang, Xiaojun Huang (), Michael Q. Zhang () and Hong Wu ()
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Lu Yang: Peking University
Fengling Chen: Tsinghua University
Haichuan Zhu: Peking University
Yang Chen: Tsinghua University
Bingjie Dong: Peking University
Minglei Shi: Tsinghua University
Weitao Wang: Peking University
Qian Jiang: National Clinical Research Center for Hematologic Disease
Leping Zhang: Peking University People’s Hospital
Xiaojun Huang: Peking-Tsinghua Center for Life Sciences
Michael Q. Zhang: Tsinghua University
Hong Wu: Peking University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 3D genome alternations can dysregulate gene expression by rewiring enhancer-promoter interactions and lead to diseases. We report integrated analyses of 3D genome alterations and differential gene expressions in 18 newly diagnosed T-lineage acute lymphoblastic leukemia (T-ALL) patients and 4 healthy controls. 3D genome organizations at the levels of compartment, topologically associated domains and loop could hierarchically classify different subtypes of T-ALL according to T cell differentiation trajectory, similar to gene expressions-based classification. Thirty-four previously unrecognized translocations and 44 translocation-mediated neo-loops are mapped by Hi-C analysis. We find that neo-loops formed in the non-coding region of the genome could potentially regulate ectopic expressions of TLX3, TAL2 and HOXA transcription factors via enhancer hijacking. Importantly, both translocation-mediated neo-loops and NUP98-related fusions are associated with HOXA13 ectopic expressions. Patients with HOXA11-A13 expressions, but not other genes in the HOXA cluster, have immature immunophenotype and poor outcomes. Here, we highlight the potentially important roles of 3D genome alterations in the etiology and prognosis of T-ALL.

Date: 2021
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DOI: 10.1038/s41467-021-24044-5

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