title: A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance.
abstract: Aberrant recruitment of histone deacetylases (HDACs) by the oncogenic fusion protein PML-RAR is involved in the pathogenesis of acute promyelocytic leukemia (APL). PML-RAR, however, is not sufficient to induce disease in mice but requires additional oncogenic lesions during the preleukemic phase. Here, we show that knock-down of Hdac1 and Hdac2 dramatically accelerates leukemogenesis in transgenic preleukemic mice. These events are not restricted to APL because lymphomagenesis driven by deletion of p53 or, to a lesser extent, by c-myc overexpression, was also accelerated by Hdac1 knock-down. In the preleukemic phase of APL, Hdac1 counteracts the activity of PML-RAR in (1) blocking differentiation; (2) impairing genomic stability; and (3) increasing self-renewal in hematopoietic progenitors, as all of these events are affected by the reduction in Hdac1 levels. This led to an expansion of a subpopulation of PML-RAR-expressing cells that is the major source of leukemic stem cells in the full leukemic stage. Remarkably, short-term treatment of preleukemic mice with an HDAC inhibitor accelerated leukemogenesis. In contrast, knock-down of Hdac1 in APL mice led to enhanced survival duration of the leukemic animals. Thus, Hdac1 has a dual role in tumorigenesis: oncosuppressive in the early stages, and oncogenic in established tumor cells.
authors: Department of Experimental Oncology at the IFOM-IEO Campus, European Institute of Oncology, via Adamello 16, Milan, Italy.
authors: Fabio
authors: F
authors: Santoro
authors: Oronza A
authors: OA
authors: Botrugno
authors: Roberto
authors: R
authors: Dal Zuffo
authors: Isabella
authors: I
authors: Pallavicini
authors: Geoffrey M
authors: GM
authors: Matthews
authors: Leonie
authors: L
authors: Cluse
authors: Iros
authors: I
authors: Barozzi
authors: Silvia
authors: S
authors: Senese
authors: Lorenzo
authors: L
authors: Fornasari
authors: Simona
authors: S
authors: Moretti
authors: Lucia
authors: L
authors: Altucci
authors: Pier Giuseppe
authors: PG
authors: Pelicci
authors: Susanna
authors: S
authors: Chiocca
authors: Ricky W
authors: RW
authors: Johnstone
authors: Saverio
authors: S
authors: Minucci
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D042822:Genomic Instability; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology* / Q000401:mortality / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D014635:Valproic Acid; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2