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 pre-leukemic phase. Here, we show that knock-down of Hdac1 and Hdac2 dramatically accelerates leukemogenesis in transgenic pre-leukemic mice. These events are not restricted to APL, since lymphomagenesis driven by deletion of p53, or to a lesser extent by c-myc overexpression, was also accelerated by Hdac1 knock-down. In the pre-leukemic phase of APL Hdac1 counter-acts the activity of PML-RAR in: i) blocking differentiation, ii) impairing genomic stability and iii) 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 pre-leukemic mice with an HDAC inhibitor accelerated leukemogenesis. In contrast, knock-down of Hdac1 in APL mice led to enhanced survival of the leukemic animals. Thus, Hdac1 has a dual role in tumorigenesis: oncosuppressive in the early stages, and oncogenic in established tumor cells.
A dual role for Hdac1 : oncosuppressor in tumorigenesis, oncogene in tumor maintenance / F. Santoro, O.A. Botrugno, R. Dal Zuffo, I. Pallavicini, G.M. Matthews, L. Cluse, I. Barozzi, S. Senese, L. Fornasari, S. Moretti, L. Altucci, P.G. Pelicci, S. Chiocca, R.W. Johnstone, S. Minucci. - In: BLOOD. - ISSN 0006-4971. - 121:17(2013 Feb 25), pp. 3459-3468. [Epub ahead of print]
|Titolo:||A dual role for Hdac1 : oncosuppressor in tumorigenesis, oncogene in tumor maintenance|
MINUCCI, SAVERIO (Ultimo)
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||25-feb-2013|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1182/blood-2012-10-461988|
|Appare nelle tipologie:||01 - Articolo su periodico|