Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia

Summary

Principal Investigator: Carlo M Croce
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2009-05-05 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc Roles of small RNAs in tumor formation
    Gianpiero Di Leva
    Ohio State University Medical Center, Department of Molecular Virology, Immunology, and Medical Genetics, 460W 12th AVE, Columbus, OH 43210, USA
    Trends Mol Med 16:257-67. 2010
  2. pmc TrxG and PcG proteins but not methylated histones remain associated with DNA through replication
    Svetlana Petruk
    Department of Biochemistry and Molecular Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Cell 150:922-33. 2012
  3. pmc Stepwise histone modifications are mediated by multiple enzymes that rapidly associate with nascent DNA during replication
    Svetlana Petruk
    Department of Biochemistry and Molecular Biology and Kimmel Cancer Center, Thomas Jefferson University, 1020 Locust Street, Philadelphia, Pennsylvania 19107, USA
    Nat Commun 4:2841. 2013

Detail Information

Publications3

  1. pmc Roles of small RNAs in tumor formation
    Gianpiero Di Leva
    Ohio State University Medical Center, Department of Molecular Virology, Immunology, and Medical Genetics, 460W 12th AVE, Columbus, OH 43210, USA
    Trends Mol Med 16:257-67. 2010
    ..A better understanding of miRNA biology might ultimately yield further insight into the molecular mechanisms of tumorigenesis and new therapeutic strategies against cancer...
  2. pmc TrxG and PcG proteins but not methylated histones remain associated with DNA through replication
    Svetlana Petruk
    Department of Biochemistry and Molecular Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Cell 150:922-33. 2012
    ..We suggest that histone modification enzymes may re-establish the histone code on newly assembled unmethylated histones and thus may act as epigenetic marks...
  3. pmc Stepwise histone modifications are mediated by multiple enzymes that rapidly associate with nascent DNA during replication
    Svetlana Petruk
    Department of Biochemistry and Molecular Biology and Kimmel Cancer Center, Thomas Jefferson University, 1020 Locust Street, Philadelphia, Pennsylvania 19107, USA
    Nat Commun 4:2841. 2013
    ..Epigenetic inheritance of gene expression patterns may require many aspects of chromatin structure to remain in close proximity to the replication complex followed by reassembly on nascent DNA shortly after replication. ..