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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Effects of SAHA alone or in combination with RA on leukemic cells from P...
Effects of SAHA alone or in combination with RA on leukemic cells from PLZF-RARα/RARα-PLZF double TM. BM cells collected from leukemic double TM were cultured at an initial cell density of 2 × 106/ml. Each sample from the leukemic transgenic mice was divided equally and incubated in parallel with or without SAHA (0.6 μM), RA (10–6 M), or the combination, as indicated. Results shown here are from one of three independent experiments performed in triplicate (mean ± SD). (a) SAHA alone causes growth inhibition and promotes RA-induced growth inhibition. 3H-Thymidine incorporation rate was measured after 44 hours’ culture as indicated above, with [3H]thymidine added for the final 24 hours. These cultures were maintained in the presence of 2% pokeweed mitogen–stimulated SCCM containing IL3 and GM-CSF). Results are expressed as percentage of inhibition upon treatment compared with untreated control. (b) SAHA alone causes apoptosis. TUNEL-positive cells were stained and scored after 48 hours of culture in the presence of SCCM and expressed as the induction of apoptosis upon treatment (untreated =1). (c) SAHA in combination with RA displays an additive effect on differentiation induction. NBT reduction assay was performed after 4 days of incubation as indicated and in the absence of SCCM. Results are expressed as the fold increase in OD540/106 cells (untreated =1).