Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy

Abstract

We investigated the effect of the histone deacetylase inhibitors (HDIs), trichostatin A and trapoxin A on leukemia cells and cell lines from the viewpoint of differentiation induction. TSA induced differentiation in erythroid cell lines by itself, whereas it synergistically enhanced the differentiation that was directed by all-trans retinoic acid (ATRA) or vitamin D3 in U937, HL60 and NB4 cells. The combined treatment of HDI with ATRA induced differentiation in ATRA-resistant HL60 and NB4 cells. The transcriptional expression during the treatment with HDI was examined in HL60, U937 and MEG-O1. Cell cycle-regulator genes (p21 waf1 and p16 INK4A ) were upregulated or constantly expressed, erythroid-specific genes (GATA-1, ␤-globin) were silent or downregulated, and housekeeping genes (␤-actin and GAPDH) were constantly expressed. Twelve of 35 (34%) clinical samples from AML patients ranging from M0 to M7 also displayed both phenotypical and morphological changes by the treatment with TSA alone. HDIs are thus the potent inducer or enhancer of differentiation in acute myeloid leukemia and regulate transcription in an ordered manner.

Histone Hyperacetylation in Mitosis Prevents Sister Chromatid Separation and Produces Chromosome Segregation Defects

“…To this aim, we inhibited histone deacetylation with TSA shortly before mitosis, rather than with long-term treatments, to avoid the known profound effects of histone deacetylase inhibition on gene expression and cell growth. Indeed, long-term treatments with histone deacetylase inhibitors have been shown to modulate gene expression (Van Lint et al, 1996), to influence acetylation of histones on promoters of target genes (Richon et al, 2000), and to promote growth arrest, differentiation, and apoptosis in different tumor cells (Kosugi et al, 1999;Saunders et al, 1999). To selectively investigate the role of histone modifications before mitosis on the fidelity of the mitotic process, the exposure regimen was built to influence histone deacetylation either during synthesis of late-replicating heterochromatic regions or during prophase mitotic condensation in exponentially growing human primary fibroblasts.…”

The t(3;21) fusion product, AML1/Evi-1 blocks AML1-induced transactivation by recruiting CtBP

“…As a control for RNA loading, the membrane was also hybridized with a mouse glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) cDNA (bottom) Dominant negative inhibition on AML1 by AML1/Evi-1 and CtBP K Izutsu et al the medium containing G-CSF, irrespective of parental cells, mock clones, or AML1/Evi-1-transfected clones, lost viability and died completely within 72 h showing morphological evidence of apoptosis in the presence of 5 ng/ml or above TSA (data not shown). Previous studies show that TSA ranging from 5 to 50 ng/ml or above is required for assessing its in vivo e ect in hematopoietic cells (Ferrara et al, 2001;Kosugi et al, 1999). At lower concentrations, TSA did not a ect the G-CSF-induced di erentiation of either 32Dcl3 clone (data not shown).…”

Transcription factors and translocations in lymphoid and myeloid leukemia

“…254 Histone deacetylase inhibitors have been found to be potent inducer/enhancers of differentiation in acute myeloid leukemia cells, and enhanced differentiation induced by ATRA therapy. 319 AML-1/CBF␣/ETO gene is both diagnostic for M2 AML and is a marker for favorable prognosis. Approximately 90% of t(8;21)-containing leukemias have been found to have FAB AML-M2 morphology and 30-40% of FAB-M2 cases have this chromosomal translocation.…”