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 ERGalt 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 DNADRE-bound DUX4HD2 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.
Highlights
Oncogenic fusions are important causes/targets in leukemia and related treatment [1, 2]
In pathogenic condition known as facioscapulohumeral muscular dystrophy (FSHD) [10], the D4Z4 repeats are contracted to 1–10
Using RNA-seq technology, we observed that the abnormal expression of Double homeobox 4 (DUX4)/IGHs often led to the overexpression of a subset of DUX4 target genes including PCDH17, STAP1, AGAP1, ERGalt, etc. (Fig. 1a)
Summary
Oncogenic fusions are important causes/targets in leukemia and related treatment [1, 2]. Very recently, using next-generation sequencing technologies, a novel B-ALL oncogenic driver DUX4/IGH, derived from. These authors contributed : Xue Dong, Weina Zhang, Haiyan Wu, Jinyan Huang. In each of the D4Z4 repeat (~3.3 kb), it constitutes a single copy of the intronless DUX4 gene. In B-cell ALL, the abnormal expression of DUX4/IGHs derived from chromosome translocation is demonstrated to be a driver factor of leukemogenesis [3]. ERGalt, derived from an abnormal transcription starting from the intron 6 of ERG, could induce lymphoid leukemia in Arf−/− mice [4]. Due to the lack of structural information, it is not clear how DUX4/IGH recognizes, binds, and activates the transcription of its target genes via the double homeobox (HD1–HD2) domain
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