Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia

A new approach to anti-leukemia therapy

H. Kosugi, M. Towatari, S. Hatano, K. Kitamura, H. Kiyoi, T. Kinoshita, M. Tanimoto, T. Murate, K. Kawashima, H. Saito, T. Naoe

Research output: Contribution to journalArticle

133 Citations (Scopus)

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-01. Cell cycle-regulator genes (p21(waf1) and p16(INK4A)) were upregulated or constantly expressed, erythroid-specific genes (GATA-1, β-globin) were silent or downregulated, and housekeeping genes (β-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.

Original languageEnglish
Pages (from-to)1316-1324
Number of pages9
JournalLeukemia
Volume13
Issue number9
Publication statusPublished - 1999
Externally publishedYes

Fingerprint

Histone Deacetylase Inhibitors
Acute Myeloid Leukemia
Leukemia
Tretinoin
HL-60 Cells
trichostatin A
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p21
Cell Line
cdc Genes
Erythroid Cells
Globins
Cholecalciferol
Essential Genes
Therapeutics
Regulator Genes
Actins
Down-Regulation
Genes

Keywords

  • Differentiation
  • Histone deacetylase inhibitor
  • Leukemia
  • Trapoxin A
  • Trichostatin A

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

Kosugi, H., Towatari, M., Hatano, S., Kitamura, K., Kiyoi, H., Kinoshita, T., ... Naoe, T. (1999). Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: A new approach to anti-leukemia therapy. Leukemia, 13(9), 1316-1324.

Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia : A new approach to anti-leukemia therapy. / Kosugi, H.; Towatari, M.; Hatano, S.; Kitamura, K.; Kiyoi, H.; Kinoshita, T.; Tanimoto, M.; Murate, T.; Kawashima, K.; Saito, H.; Naoe, T.

In: Leukemia, Vol. 13, No. 9, 1999, p. 1316-1324.

Research output: Contribution to journalArticle

Kosugi, H, Towatari, M, Hatano, S, Kitamura, K, Kiyoi, H, Kinoshita, T, Tanimoto, M, Murate, T, Kawashima, K, Saito, H & Naoe, T 1999, 'Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: A new approach to anti-leukemia therapy', Leukemia, vol. 13, no. 9, pp. 1316-1324.
Kosugi, H. ; Towatari, M. ; Hatano, S. ; Kitamura, K. ; Kiyoi, H. ; Kinoshita, T. ; Tanimoto, M. ; Murate, T. ; Kawashima, K. ; Saito, H. ; Naoe, T. / Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia : A new approach to anti-leukemia therapy. In: Leukemia. 1999 ; Vol. 13, No. 9. pp. 1316-1324.
@article{f2b7e489802941d9a711bf1fd715f454,
title = "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-01. Cell cycle-regulator genes (p21(waf1) and p16(INK4A)) were upregulated or constantly expressed, erythroid-specific genes (GATA-1, β-globin) were silent or downregulated, and housekeeping genes (β-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.",
keywords = "Differentiation, Histone deacetylase inhibitor, Leukemia, Trapoxin A, Trichostatin A",
author = "H. Kosugi and M. Towatari and S. Hatano and K. Kitamura and H. Kiyoi and T. Kinoshita and M. Tanimoto and T. Murate and K. Kawashima and H. Saito and T. Naoe",
year = "1999",
language = "English",
volume = "13",
pages = "1316--1324",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia

T2 - A new approach to anti-leukemia therapy

AU - Kosugi, H.

AU - Towatari, M.

AU - Hatano, S.

AU - Kitamura, K.

AU - Kiyoi, H.

AU - Kinoshita, T.

AU - Tanimoto, M.

AU - Murate, T.

AU - Kawashima, K.

AU - Saito, H.

AU - Naoe, T.

PY - 1999

Y1 - 1999

N2 - 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-01. Cell cycle-regulator genes (p21(waf1) and p16(INK4A)) were upregulated or constantly expressed, erythroid-specific genes (GATA-1, β-globin) were silent or downregulated, and housekeeping genes (β-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.

AB - 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-01. Cell cycle-regulator genes (p21(waf1) and p16(INK4A)) were upregulated or constantly expressed, erythroid-specific genes (GATA-1, β-globin) were silent or downregulated, and housekeeping genes (β-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.

KW - Differentiation

KW - Histone deacetylase inhibitor

KW - Leukemia

KW - Trapoxin A

KW - Trichostatin A

UR - http://www.scopus.com/inward/record.url?scp=0032879920&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032879920&partnerID=8YFLogxK

M3 - Article

VL - 13

SP - 1316

EP - 1324

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 9

ER -