title: ZRF1 controls the retinoic acid pathway and regulates leukemogenic potential in acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in transcriptional regulation, is highly overexpressed in human AML, but it is not known whether it plays a role in leukemia progression. Here, we demonstrate that ZRF1 depletion decreases cell proliferation, induces apoptosis and enhances cell differentiation in human AML cells. Treatment with retinoic acid (RA), a differentiating agent currently used to treat certain AMLs, leads to a functional switch of ZRF1 from a negative regulator to an activator of differentiation. At the molecular level, ZRF1 controls the RA-regulated gene network through its interaction with the RA receptor α (RARα) and its binding to RA target genes. Our genome-wide expression study reveals that ZRF1 regulates the transcription of nearly half of RA target genes. Consistent with our in vitro observations that ZRF1 regulates proliferation, apoptosis, and differentiation, ZRF1 depletion strongly inhibits leukemia progression in a xenograft mouse model. Finally, ZRF1 knockdown cooperates with RA treatment in leukemia suppression in vivo. Taken together, our data reveal that ZRF1 is a key transcriptional regulator in leukemia progression and suggest that ZRF1 inhibition could be a novel strategy to be explored for AML treatment.
authors.affiliation: 1] Centre de Regulació Genòmica (CRG), Barcelona, Spain [2] UPF, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Demajo
authors.affiliation: 1] Centre de Regulació Genòmica (CRG), Barcelona, Spain [2] UPF, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Uribesalgo
authors.affiliation: 1] Centre de Regulació Genòmica (CRG), Barcelona, Spain [2] UPF, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gutiérrez
authors.affiliation: 1] Centre de Regulació Genòmica (CRG), Barcelona, Spain [2] UPF, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Ballaré
authors.affiliation: Unidad de Animal de Laboratorio, PRBB, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Capdevila
authors.affiliation: Institute of Molecular Pathology (IMP), Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Roth
authors.affiliation: Institute of Molecular Pathology (IMP), Vienna, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Unidad de Animal de Laboratorio, PRBB, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Martín-Caballero
authors.affiliation: 1] Centre de Regulació Genòmica (CRG), Barcelona, Spain [2] UPF, Barcelona, Spain [3] Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Di Croce
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D018832:Molecular Chaperones; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C414672:DNAJC2 protein, human; D018832:Molecular Chaperones; D015513:Oncogene Proteins; D016601:RNA-Binding Proteins; D014212:Tretinoin