3′utr-mediated gene silencing of the mixed lineage leukemia (mll) gene3u2032utr-mediated基因沉默的混合血统白血病mll基因.pdfVIP

39UTR-Mediated Gene Silencing of the Mixed Lineage Leukemia (MLL) Gene 1,2 1 1 2 Maria Gomez-Benito , Fabricio Loayza-Puch , Joachim Oude Vrielink , Maria D. Odero , Reuven Agami1,3* 1 Division of Gene Regulation The Netherlands Cancer Institute, Amsterdam, The Netherlands, 2 Center for Applied Medical Research, Pamplona, Spain, 3 Center for Biomedical Genetics, Utrecht, The Netherlands Abstract Translocations involving the Mixed Lineage Leukemia (MLL) gene generate in-frame fusions of MLL with more than 50 different partner genes (PGs). Common to all MLL translocations is the exchange not only of coding regions, but also of MLL and PG 39-untranslated regions (39UTRs). As a result, the MLL-PG fusion is normally highly expressed and considered the main driver of leukemia development, whereas the function of the PG-MLL fusions in leukemic disease is unclear. As 39UTRs have been recognized as determinant regions for regulation of gene expression, we hypothesized that loss of the MLL 39UTR could have a role in generating high MLL-PG levels and leukemia development. Here, we first tested the MLL-PG and PG-MLL mRNA levels in different leukemic cells and tumours and uncovered differential expression that indicates strong repression by the MLL-39UTR. Reporter assays confirmed that the 39UTR of MLL, but not of its main PGs, harbours a region that imposes a strong gene silencing effect. Gene suppression by the MLL 3 9UTR was largely microRNA independent and did not affect mRNA stability, but inhibited transcription. This effect can at least partially be attributed to a tighter interaction of the MLL 39UTR with RNA polymerase II than PG 39UTRs, affecting its phosphorylation state. Altog