Journal
LEUKEMIA
Volume 32, Issue 6, Pages 1466-1476Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41375-018-0093-1
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Funding
- National Natural Scientific Foundation of China [81770142, 81370620, 81570120, 31070645]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine [20152504]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institute of Higher Learning
- SMSTC [11JC1407200]
- SME [12ZZ109]
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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.
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