7X1N

Crystal structure of MEF2D-MRE complex

Summary for 7X1N

• Entry DOI: 10.2210/pdb7x1n/pdb
• Descriptor: DNA (5'-D(P*AP*AP*CP*TP*AP*TP*TP*TP*AP*TP*AP*AP*G)-3'), DNA (5'-D(P*TP*CP*TP*TP*AP*TP*AP*AP*AP*TP*AP*GP*T)-3'), Myocyte enhancer factor 2D/deleted in azoospermia associated protein 1 fusion protein, ... (4 entities in total)
• Functional Keywords: acute lymphoblastic leukemia, mef2d-fusions, mef2d-hnrnpul1, mef2d-dna interaction, leukemogenesis, prognostic markers, transcription-dna complex, transcription/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 63892.72

Authors

Zhang, H.,Zhang, M.,Wang, Q.Q.,Chen, Z.,Chen, S.J.,Meng, G. (deposition date: 2022-02-24, release date: 2022-05-25, Last modification date: 2023-11-29)

Primary citation

Zhang, M.,Zhang, H.,Li, Z.,Bai, L.,Wang, Q.,Li, J.,Jiang, M.,Xue, Q.,Cheng, N.,Zhang, W.,Mao, D.,Chen, Z.,Huang, J.,Meng, G.,Chen, Z.,Chen, S.J.
Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion.
Blood, 140:1390-1407, 2022

PubMed Abstract: Recurrent MEF2D fusions with poor prognosis have been identified in B-cell precursor ALL (BCP-ALL). The molecular mechanisms underlying the pathogenic function of MEF2D fusions are poorly understood. Here, we show that MEF2D-HNRNPUL1 (MH) knock-in mice developed a progressive disease from impaired B-cell development at the pre-pro-B stage to pre-leukemia over 10 to 12 months. When cooperating with NRASG12D, MH drove an outbreak of BCP-ALL, with a more aggressive phenotype than the NRASG12D-induced leukemia. RNA-sequencing identified key networks involved in disease mechanisms. In chromatin immunoprecipitation-sequencing experiments, MH acquired increased chromatin-binding ability, mostly through MEF2D-responsive element (MRE) motifs in target genes, compared with wild-type MEF2D. Using X-ray crystallography, the MEF2D-MRE complex was characterized in atomic resolution, whereas disrupting the MH-DNA interaction alleviated the aberrant target gene expression and the B-cell differentiation arrest. The C-terminal moiety (HNRNPUL1 part) of MH was proven to contribute to the fusion protein's trans-regulatory activity, cofactor recruitment, and homodimerization. Furthermore, targeting MH-driven transactivation of the HDAC family by using the histone deacetylase inhibitor panobinostat in combination with chemotherapy improved the overall survival of MH/NRASG12D BCP-ALL mice. Altogether, these results not only highlight MH as an important driver in leukemogenesis but also provoke targeted intervention against BCP-ALL with MEF2D fusions.

PubMed: 35544603
DOI: 10.1182/blood.2022016241

Experimental method

X-RAY DIFFRACTION (3.315 Å)