Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia
Li-Zhen He, … , Victoria M. Richon, Pier Paolo Pandolfi
Li-Zhen He, … , Victoria M. Richon, Pier Paolo Pandolfi
Published November 1, 2001
Citation Information: J Clin Invest. 2001;108(9):1321-1330. https://doi.org/10.1172/JCI11537.
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Article

Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia

Abstract

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations, invariably involving the retinoic acid receptor α (RARα) gene fused to one of several distinct loci, including the PML or PLZF genes, involved in t(15;17) or t(11;17), respectively. Patients with t(15;17) APL respond well to retinoic acid (RA) and other treatments, whereas those with t(11;17) APL do not. The PML-RARα and PLZF-RARα fusion oncoproteins function as aberrant transcriptional repressors, in part by recruiting nuclear receptor-transcriptional corepressors and histone deacetylases (HDACs). Transgenic mice harboring the RARα fusion genes develop forms of leukemia that faithfully recapitulate both the clinical features and the response to RA observed in humans with the corresponding translocations. Here, we investigated the effects of HDAC inhibitors (HDACIs) in vitro and in these animal models. In cells from PLZF-RARα/RARα-PLZF transgenic mice and cells harboring t(15;17), HDACIs induced apoptosis and dramatic growth inhibition, effects that could be potentiated by RA. HDACIs also increased RA-induced differentiation. HDACIs, but not RA, induced accumulation of acetylated histones. Using microarray analysis, we identified genes induced by RA, HDACIs, or both together. In combination with RA, all HDACIs tested overcame the transcriptional repression exerted by the RARα fusion oncoproteins. In vivo, HDACIs induced accumulation of acetylated histones in target organs. Strikingly, this combination of agents induced leukemia remission and prolonged survival, without apparent toxic side effects.

Authors

Li-Zhen He, Thomas Tolentino, Peter Grayson, Sue Zhong, Raymond P. Warrell Jr., Richard A. Rifkind, Paul A. Marks, Victoria M. Richon, Pier Paolo Pandolfi

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The effects of HDACIs alone and in combination with RA on NB4 cell growt...
The effects of HDACIs alone and in combination with RA on NB4 cell growth, apoptosis, and differentiation. (a) Structures of the HDACIs utilized in this study. (b) NB4 cells cultured at an initial cell density of 105/ml in the presence of PB, TSA, or SAHA alone and in combination with RA (10–6 M). Growth curves were performed on NB4 cells cultured with 1 mM PB, 0.12 μM TSA, or 0.6 μM SAHA alone or in combination with RA. (c) 3H-Thymidine incorporation was assayed after 20 hours’ culture with PB, TSA, or SAHA at the indicated concentrations and in combination with RA (10–6 M) and a further 24 hours with 3H-Thymidine. Each point represents results from three independent experiments performed in triplicate for b and c (mean ± SD). (d) The percentage of apoptotic cells was measured after 48 hours’ culture by using flow cytometry analysis of Annexin V–labeled cells. Each point represents results from three independent experiments performed in duplicate (mean ± SD). (e) The NBT reduction assay was performed after 4 days of culture and measured as OD540nm/106 cells. Each point represents results from three independent experiments performed in duplicate (mean ± SD). The OD540nm value induced by various HDACIs with or without 10–6 M RA normalized to untreated control (untreated = 1).