A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance
Menée à l'aide de modèles murins de leucémie aiguë promyélocytaire, cette étude montre que l'histone désacétylase Hdac1 joue un rôle de suppresseur de tumeurs dans les phases précoces de la maladie et un rôle oncogénique lorsque la maladie est établie
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.
Blood 2013