Structural basis of DUX4/IGH-driven transactivation

Xue Dong; Weina Zhang; Haiyan Wu; Jinyan Huang; Ming Zhang; Pengran Wang; Hao Zhang; Zhu Chen; Sai-Juan Chen; Guoyu Meng

doi:10.1038/s41375-018-0093-1

Structural basis of DUX4/IGH-driven transactivation

Leukemia. 2018 Jun;32(6):1466-1476. doi: 10.1038/s41375-018-0093-1. Epub 2018 Mar 15.

Authors

Xue Dong^{1

2}, Weina Zhang^{1

2}, Haiyan Wu^{1

2}, Jinyan Huang^{1

2}, Ming Zhang^{1

2}, Pengran Wang^{1

2}, Hao Zhang^{1

2}, Zhu Chen^{1

2}, Sai-Juan Chen^{3

4}, Guoyu Meng^{5

6}

Affiliations

¹ State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai JiaoTong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai JiaoTong University, 197 Ruijin Er Road, Shanghai, 200025, China.
² Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai JiaoTong University, 800 Dong Chuan Road, Shanghai, 200240, China.
³ State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai JiaoTong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai JiaoTong University, 197 Ruijin Er Road, Shanghai, 200025, China. sjchen@stn.sh.cn.
⁴ Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai JiaoTong University, 800 Dong Chuan Road, Shanghai, 200240, China. sjchen@stn.sh.cn.
⁵ State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai JiaoTong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai JiaoTong University, 197 Ruijin Er Road, Shanghai, 200025, China. guoyumeng@shsmu.edu.cn.
⁶ Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai JiaoTong University, 800 Dong Chuan Road, Shanghai, 200240, China. guoyumeng@shsmu.edu.cn.

Abstract

Oncogenic fusions are major drivers in leukemogenesis and may serve as potent targets for treatment. DUX4/IGHs have been shown to trigger the abnormal expression of ERG_alt through binding to DUX4-Responsive-Element (DRE), which leads to B-cell differentiation arrest and a full-fledged B-ALL. Here, we determined the crystal structures of Apo- and DNA_DRE-bound DUX4_HD2 and revealed a clamp-like transactivation mechanism via the double homeobox domain. Biophysical characterization showed that mutations in the interacting interfaces significantly impaired the DNA binding affinity of DUX4 homeobox. These mutations, when introduced into DUX4/IGH, abrogated its transactivation activity in Reh cells. More importantly, the structure-based mutants significantly impaired the inhibitory effects of DUX4/IGH upon B-cell differentiation in mouse progenitor cells. All these results help to define a key DUX4/IGH-DRE recognition/step in B-ALL.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B-Lymphocytes / cytology
Cell Differentiation
Crystallization
DNA / metabolism
Homeodomain Proteins / chemistry*
Humans
Immunoglobulin Heavy Chains / chemistry*
Mutation
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
Protein Domains
Transcriptional Activation*

Substances

DUX4L1 protein, human
Homeodomain Proteins
Immunoglobulin Heavy Chains
DNA