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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In vivo effects of SAHA, RA, and the combination of both on PLZF-RARα/RA...
In vivo effects of SAHA, RA, and the combination of both on PLZF-RARα/RARα-PLZF double leukemic TM. (a) Western blot analysis of acetylated histone H4 in murine cells upon in vivo administration of SAHA. Wild-type and leukemic TM were given SAHA (20 μg/gbw) by intraperitoneal injection. Histones were acid extracted from murine peripheral blood, BM, and spleen cells in untreated mice and 2 hours after SAHA administration. (b) SAHA in combination with RA treatment prolongs survival in PLZF-RARα/RARα-PLZF double TM with leukemia. Upon presentation of leukemia as monitored by automatic and differentiated counts on peripheral blood samples from PLZF-RARα/RARα-PLZF double TM, RA was administered daily at a dose of 1.5 μg/gbw for 2 weeks. The RA-treated mice were then randomly assigned into three groups: RA alone (1.5 μg/gbw), SAHA (50 μg/gbw) alone, and SAHA (50 μg/gbw) in combination with RA (1.5 μg/gbw). The treatment was continued for 4 weeks. During and after the treatment, the mice were bled weekly, and automatic and morphological differential counts were performed on each sample to evaluate response to treatment until each animal died. Kaplan Meier analysis was used to compare the cumulative survival period between SAHA in combination with RA (n = 11) and RA (n = 9) or SAHA (n = 6) alone. The black bar on the abscissa represents the 28-day period of treatment. Survival time reflects the days from the initiation of therapies until death for each mouse. (c) Complete remission was induced by SAHA + RA treatment in six of 11 leukemic PLZF-RARα/RARα-PLZF double transgenic mice. Analyses were performed weekly as described above. SAHA + RA causes the same duration of disease-free survival (time in remission) in PLZF-RARα/RARα-PLZF leukemic mice as that achieved in PML-RARα transgenic leukemic mice treated with RA (1.5 μg/gbw).