The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin

被引:93
作者
Zeisig, DT
Bittner, CB
Zeisig, BB
García-Cuéllar, MP
Hess, JL
Slany, RK
机构
[1] Univ Erlangen Nurnberg, Dept Genet, D-91058 Erlangen, Germany
[2] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
关键词
ENL; MLL; leukemia; histone; chromatin;
D O I
10.1038/sj.onc.1208699
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mixed lineage leukemia (MLL) fusion proteins are derived from translocations at 11q23 that occur in aggressive subtypes of leukemia. As a consequence, MLL is joined to different unrelated proteins to form oncogenic transcription factors. Here we demonstrate a direct interaction between several nuclear MLL fusion partners and present evidence for a role of these proteins in histone binding. In two-hybrid studies, ENL interacted with AF4 and AF5q31 as well as with a fragment of AF10. A structure-function analysis revealed that the AF4/AF5q31/AF10 binding domain in ENL coincided with the C-terminus that is essential for transformation by MLL-ENL. The ENL/AF4 association was corroborated by GST-pulldown experiments and by mutual coprecipitation. Both proteins colocalized in vivo in a nuclear speckled pattern. Moreover, AF4 and ENL coeluted on sizing columns together with the known ENL binding partner Polycomb3, suggesting the presence of a multiprotein complex. The overexpression of ENL alone activated a reporter construct and a mutational screen indicated the conserved YEATS domain as essential for this function. Overlay and pulldown-assays finally showed a specific and YEATS domain-dependent association of ENL with histones H3 and H1. In summary, our studies support a common role for nuclear MLL fusion partners in chromatin biology.
引用
收藏
页码:5525 / 5532
页数:8
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