First Author | Leiva M | Year | 2012 |
Journal | Leukemia | Volume | 26 |
Issue | 7 | Pages | 1630-7 |
PubMed ID | 22333881 | Mgi Jnum | J:190780 |
Mgi Id | MGI:5449682 | Doi | 10.1038/leu.2012.39 |
Citation | Leiva M, et al. (2012) Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL. Leukemia 26(7):1630-7 |
abstractText | Aberrant histone acetylation was physiopathologically associated with the development of acute myeloid leukemias (AMLs). Reversal of histone deacetylation by histone deacetylase inhibitor (HDACis) activates a cell death program that allows tumor regression in mouse models of AMLs. We have used several models of PML-RARA-driven acute promyelocytic leukemias (APLs) to analyze the in vivo effects of valproic acid, a well-characterized HDACis. Valproic acid (VPA)-induced rapid tumor regression and sharply prolonged survival. However, discontinuation of treatment was associated to an immediate relapse. In vivo, as well as ex vivo, VPA-induced terminal granulocytic differentiation. Yet, despite full differentiation, leukemia-initiating cell (LIC) activity was actually enhanced by VPA treatment. In contrast to all-trans retinoic acid (ATRA) or arsenic, VPA did not degrade PML-RARA. However, in combination with ATRA, VPA synergized for PML-RARA degradation and LIC eradication in vivo. Our studies indicate that VPA triggers differentiation, but spares LIC activity, further uncouple differentiation from APL clearance and stress the importance of PML-RARA degradation in APL cure. |