A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance.

Fabio Santoro, Oronza A. Botrugno, Roberto Dal Zuffo, Isabella Pallavicini, Geoffrey M. Matthews, Leonie Cluse, Iros Barozzi, Silvia Senese, Lorenzo Fornasari, Simona Moretti, Lucia Altucci, Pier Giuseppe Pelicci, Susanna Chiocca, Ricky W. Johnstone, Saverio Minucci

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3459-3468
Number of pages10
JournalBlood
Volume121
Issue number17
DOIs
Publication statusPublished - Apr 25 2013

    Fingerprint

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Santoro, F., Botrugno, O. A., Dal Zuffo, R., Pallavicini, I., Matthews, G. M., Cluse, L., Barozzi, I., Senese, S., Fornasari, L., Moretti, S., Altucci, L., Pelicci, P. G., Chiocca, S., Johnstone, R. W., & Minucci, S. (2013). A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance. Blood, 121(17), 3459-3468. https://doi.org/10.1182/blood-2012-10-461988