Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy.
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 (p21waf1 and p16INK4A) were upregulated or constantly expressed, erythroid-specific genes (GATA-1, beta-globin) were silent or downregulated, and housekeeping genes (beta-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.
Kosugi
H
H
First Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Towatari
M
M
Hatano
S
S
Kitamura
K
K
Kiyoi
H
H
Kinoshita
T
T
Tanimoto
M
M
Murate
T
T
Kawashima
K
K
Saito
H
H
Naoe
T
T
D016475:3T3 Cells; D000208:Acute Disease; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015672:Erythroid Precursor Cells / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000627:therapeutic use; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D008533:Megakaryocytes / Q000187:drug effects; D051379:Mice; D010455:Peptides; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010455:Peptides; C067070:trapoxin A; C012589:trichostatin A