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), tr ichostatin A and trapoxin A on leukemia cells and cell lines from the viewp oint of differentiation induction. TSA induced differentiation in erythroid cell lines by itself, whereas it synergistically enhanced the differentiat ion that was directed by all-trans retinoic acid (ATRA) or vitamin D3 in U9 37, HL60 and NB4 cells. The combined treatment of HDI with ATRA induced dif ferentiation in ATRA-resistant HL60 and NB4 cells. The transcriptional expr ession 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, beta-globin) were s ilent or downregulated, and housekeeping genes (beta-actin and GAPDH) were constantly expressed. Twelve of 35 (34%) clinical samples from AML patients ranging from NIO to M7 also displayed both phenotypical end morphological changes by the treatment with TSA alone. HDIs are thus the potent inducer o r enhancer of differentiation in acute myeloid leukemia and regulate transc ription in an ordered manner.