title: PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL.
abstract: Proteins involved in DNA double-strand break (DSB) repair localize within the promyelocytic leukemia nuclear bodies (PML-NBs), whose disruption is at the root of the acute promyelocytic leukemia (APL) pathogenesis. All-trans-retinoic acid (RA) treatment induces PML-RARα degradation, restores PML-NB functions, and causes terminal cell differentiation of APL blasts. However, the precise role of the APL-associated PML-RARα oncoprotein and PML-NB integrity in the DSB response in APL leukemogenesis and tumor suppression is still lacking. Primary leukemia blasts isolated from APL patients showed high phosphorylation levels of H2AX (γ-H2AX), an initial DSBs sensor. By addressing the consequences of ionizing radiation (IR)-induced DSB response in primary APL blasts and RA-responsive and -resistant myeloid cell lines carrying endogenous or ectopically expressed PML-RARα, before and after treatment with RA, we found that the disruption of PML-NBs is associated with delayed DSB response, as revealed by the impaired kinetic of disappearance of γ-H2AX and 53BP1 foci and activation of ATM and of its substrates H2AX, NBN, and CHK2. The disruption of PML-NB integrity by PML-RARα also affects the IR-induced DSB response in a preleukemic mouse model of APL in vivo. We propose the oncoprotein-dependent PML-NB disruption and DDR impairment as relevant early events in APL tumorigenesis.
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Rome 00146, Italy.|Istituto Nazionale di Biostrutture e Biosistemi, Viale Medaglie d'Oro 305, Rome 00136, Italy.
authors.forename: A
authors.initials: A
authors.lastname: di Masi
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Rome 00146, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Cilli
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Rome 00146, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Berardinelli
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Rome 00146, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Talarico
authors.affiliation: IFOM-IEO Campus, Via Adamello 16, Milan 20139, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Pallavicini
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Rome 00146, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Pennisi
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Rome 00146, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Leone
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Rome 00146, Italy.|Istituto Nazionale di Biostrutture e Biosistemi, Viale Medaglie d'Oro 305, Rome 00136, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Antoccia
authors.affiliation: Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy.|Neuro-Oncoematology Unit, Santa Lucia Foundation, Rome, Italy.
authors.forename: N I
authors.initials: NI
authors.lastname: Noguera
authors.affiliation: Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy.|Neuro-Oncoematology Unit, Santa Lucia Foundation, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Lo-Coco
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Rome 00146, Italy.|Istituto Nazionale di Biostrutture e Biosistemi, Viale Medaglie d'Oro 305, Rome 00136, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ascenzi
authors.affiliation: IFOM-IEO Campus, Via Adamello 16, Milan 20139, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, University of Rome 'La Sapienza', Corso della Repubblica 79, Latina 04100, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Nervi
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects / Q000648:ultrastructure; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004195:Disease Models, Animal; D005720:Gamma Rays; D015973:Gene Expression Regulation, Leukemic; D042381:Granulocyte Precursor Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; C112156:NBN protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D004247:DNA; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human