ALL1-associated leukemias account for the majority of infant and therapy-related leukemias. ALL1 is the human homologue of Drosophila TRITHORAX (TRX) which has a critical role in setting up the body pattern during embryonic development. C. Croce and E. Canaani are the co-discoverers of ALL1, and A. Mazo is the discoverer of TRX. Our goal is to further understand how ALL1 fusion proteins trigger leukemia. Because of the strong homology in structure and function between ALL1 and TRX, investigations of TRX have yielded unexpected important insights pertinent not only for TRX, but for ALL1 as well. Major achievements we made recently include: 1) ALL1 fusion proteins bind together with the microRNAs processor enzyme Drosha to miR-191 to upregulate its expression, 2) knockdown of MEIS1 and HOX A10 or A9 in an ALL1-associated leukemic cell line impairs its leukemogenicity, 3) indispensable role of TRX in transcriptional elongation and in recruitment of elongation factors, 4) a role of TRX-dependent transcription of non-coding sequences upstream to the ubx genes in inhibiting expression of ubx coding region, 5) co-recruitment of normal partner proteins with ALL1 fusions to targets of the latter, 6) potential role for TRX and ALL1 in Epigenetic inheritance. In our studies we use highly sophisticated and varied methodologies, including genome-wide location analysis, genome-wide expression profiling, purification of multiprotein complexes and characterization of their components by mass spectroscopy, assaying microRNAs processing in vitro and in vivo, applying array screening to examine expression of microRNAs, lentiviral-based transduction of shRNAs into hematopoietic cells, assaying homing, migration and engraftment of manipulated leukemic cells, separating Drosophila embryo nuclei that express a TRX target from those nuclei that do not, etc. We strongly believe that such a wide-angle attack on the issues of ALL1/TRX and ALL1 leukemogenesis will provide deeper understanding and new vision of the fundamentals of gene fusion-mediated leukemogenesis and of gene regulation.
Patients with ALL1-associated leukemias, in particular infants who constitute the largest group at risk, have dismal prognosis. The failure to improve prognosis with either chemotherapy or bonemarrow transplantation calls for devising innovative new therapies. Those would likely be based on recognition of the molecules critical for pathogenesis. Much of this proposal aims on identification of such molecules.
|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|
|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|
|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|
|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|
|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|
|Petruk, Svetlana; Sedkov, Yurii; Johnston, Danika M et al. (2012) TrxG and PcG proteins but not methylated histones remain associated with DNA through replication. Cell 150:922-33|
|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|
|Iorio, Marilena V; Croce, Carlo M (2012) Causes and consequences of microRNA dysregulation. Cancer J 18:215-22|
|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|
Showing the most recent 10 out of 33 publications