title: Epigenetic mechanisms in leukemia.
abstract: Focal organization of regulatory machinery within the interphase nucleus is linked to biological responsiveness and perturbed in cancer. Lineage determinant Runx proteins organize and assemble multi-protein complexes at sites of transcription within the nucleus and regulate both RNA polymerase II- and I-mediated gene expression. In addition, Runx proteins epigenetically control lineage determining transcriptional programs including: 1) architectural organization of macromolecular complexes in interphase, 2) regulation of gene expression through bookmarking during mitosis, and 3) microRNA-mediated translational control in the interphase nucleus. These mechanisms are compromised with the onset and progression of cancer. For example, the oncogenic AML1-ETO protein, which results from a chromosomal translocation between chromosomes 8 and 21, is expressed in nearly 25% of all acute myelogenous leukemias, disrupts Runx1 subnuclear localization during interphase and compromises transcriptional regulation. Epigenetically, the leukemic protein redirects the Runx1 DNA binding domain to leukemia-specific nuclear microenvironments, modifies regulatory protein accessibility to Runx1 target genes by imprinting repressive chromatin marks, and deregulates the microRNA (miR) profile of diseased myeloid cells. Consequently, the entire Runx1-dependent transcriptional program of myeloid cells is deregulated leading to onset and progression of acute myeloid leukemia and maintenance of leukemic phenotype. We discuss the potential of modified epigenetic landscape of leukemic cells as a viable therapeutic target.
authors.affiliation: Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Ave. N., Worcester, MA 01655, USA.
authors.forename: Sayyed K
authors.initials: SK
authors.lastname: Zaidi
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Trombly
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Dowdy
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
mesh_terms: D002467:Cell Nucleus / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D044127:Epigenesis, Genetic; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis; D008957:Models, Genetic; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D050436:Regulatory Elements, Transcriptional; D014178:Translocation, Genetic; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: C107844:AML1-ETO fusion protein, human; D002843:Chromatin; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D012334:RNA, Neoplasm; D022661:RNA, Untranslated; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human