The ALL1/MLL gene human homologue of Drosphila TRXwas previously cloned by us by virtue of its rearrangement in infant and therapy-related acute leukemia, resulting in fusion of the gene to a variety of partner genes, or in partial tandem duplication (self fusion). The ensuing fusion genes encode chimeric ALL1 proteins which directly trigger the disease. The normal ALL1 protein was shown by us to be a histone H3-lysine 4 methyltransferase which binds to its target genes to activate their expression. This proposal is based on our recent studies suggesting co-recruitment of the normal partner proteins with ALL1 fusions, identification of primary targets of ALL1 fusions, demonstrating that the UTX H3K27me3 demethylase acts in upregulation of /-/ox genes, and showing that ASH 1, like ALL1, is an H3K4 methytransferase and shares with ALL1 all targets examined. The main directions proposed will be to inquire whether the normal AF4/ENL/AF9 transeriptional elongation complex is co-recruited with all and/or some ALL1 fusions, to apply the new methodology of ChlPSeq for identification and comparison of ALL1 fusions and ALL1 targets, to check selected ALL1 fusions'targets for direct role in leukemogenicity, to examine whether H3K27me3 demethylases have a role in modulating (Hox) expression in hematopoietic cells, including those producing ALL1 fusions, further investigate function of ASH1 compared to ALL1, and ascertain whether ALL1 and not H3K4me3 is the carrier of epigenetic inheritance.
In this proposal we focus on ALL1-associated leukemias which carry a grim prognosis. The frequent failure of treatment, and the additional suffering involved due to the very young age of many of the patients, calls for attempts to develop new drugs based on recognition of the proteins with a direct role in the disease. Identification of these proteins is a major theme of this proposal.
|Nakanishi, H; Taccioli, C; Palatini, J et al. (2014) Loss of miR-125b-1 contributes to head and neck cancer development by dysregulating TACSTD2 and MAPK pathway. Oncogene 33:702-12|
|Di Leva, Gianpiero; Garofalo, Michela; Croce, Carlo M (2014) MicroRNAs in cancer. Annu Rev Pathol 9:287-314|
|Di Leva, Gianpiero; Piovan, Claudia; Gasparini, Pierluigi et al. (2013) Estrogen mediated-activation of miR-191/425 cluster modulates tumorigenicity of breast cancer cells depending on estrogen receptor status. PLoS Genet 9:e1003311|
|Carbonell, Albert; Mazo, Alexander; Serras, Florenci et al. (2013) Ash2 acts as an ecdysone receptor coactivator by stabilizing the histone methyltransferase Trr. Mol Biol Cell 24:361-72|
|Petruk, Svetlana; Black, Kathryn L; Kovermann, Sina K et al. (2013) Stepwise histone modifications are mediated by multiple enzymes that rapidly associate with nascent DNA during replication. Nat Commun 4:2841|
|Manfè, Valentina; Biskup, Edyta; Willumsgaard, Ayalah et al. (2013) cMyc/miR-125b-5p signalling determines sensitivity to bortezomib in preclinical model of cutaneous T-cell lymphomas. PLoS One 8:e59390|
|Quintavalle, C; Garofalo, M; Zanca, C et al. (2012) miR-221/222 overexpession in human glioblastoma increases invasiveness by targeting the protein phosphate PTP?. Oncogene 31:858-68|
|Acunzo, M; Visone, R; Romano, G et al. (2012) miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222. Oncogene 31:634-42|
|Garofalo, M; Quintavalle, C; Romano, G et al. (2012) miR221/222 in cancer: their role in tumor progression and response to therapy. Curr Mol Med 12:27-33|
|Iorio, Marilena V; Croce, Carlo M (2012) Causes and consequences of microRNA dysregulation. Cancer J 18:215-22|
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