Akihiko Yokoyama and Michael Cleary hypothesised that menin might transiently recruit other factors to the MLL–menin complex. To look for weakly associated proteins, they purified the complex from cells transiently overexpressing the oncogenic MLL fusion protein MLL–ENL (also known as MLLT1) and menin using one-step affinity purification. They identified lens epithelium-derived growth factor (LEDGF, also known as PSIP1), a nuclear protein involved in transcriptional coactivation. Further experiments confirmed this association and showed that LEDGF can only bind the MLL–ENL–menin complex, but not MLL-ENL or menin individually.
In normal cells, the MLL–menin complex controls the expression of a number of genes involved in negatively regulating the cell cycle, as well as homeobox (Hox) genes. Chromatin immunoprecipitation analyses indicated that LEDGF co-localizes with MLL–menin complexes on target genes, regardless of whether MLL is present as the wild-type protein or as an oncogenic fusion protein. Moreover, MLL–ENL deletion mutants that could not interact with LEDGF, but were still able to bind menin, were unable to transform myeloid progenitor cells, and did not increase expression of Hoxa9. Short hairpin RNAs that target Ledgf further showed that LEDGF is required for the maintenance of leukaemic transformation induced by MLL–ENL. So, what does recruitment of LEDGF enable?
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