1. ¹Dipartimento di Patologia e Oncologia Sperimentali, Università degli Studi di Firenze, Firenze, Italy
2. ²UF Ematologia, Università degli Studi di Firenze, AOU Careggi, Firenze, Italy
3. ³Italfarmaco S.p.A., Milano, Italy
4. ⁴Department of Medicine, University of Freiburg, Freiburg, Germany

Correspondence: Professor V Santini, UF di Ematologia, Università degli Studi di Firenze, AOU Careggi, Viale GB Morgagni 85, Firenze 50134, Italy. E-mail: santini@unifi.it

Received 5 April 2007; Revised 16 July 2007; Accepted 16 August 2007; Published online 24 September 2007.

Abstract

We analysed the in vitro effects of a new hydroxamate derivative, ITF2357, on AML cells. ITF2357 potently induced histone acetylation. ITF2357 0.1 M blocked proliferation and induced apoptosis in AML1/ETO-positive Kasumi-1 cells, while AML1/ETO-negative HL60, THP1 and NB4 cell lines were sensitive only to 1 M ITF2357. Apoptosis was induced by 0.1 M ITF2357 in AML1/ETO-positive primary blasts and U937-A/E cells induced to express AML1/ETO, but not in U937-A/E cells non-expressing AML1/ETO. In Kasumi-1 cells 0.1 M ITF2357 induced AML1/ETO degradation through a caspase-dependent mechanism. ITF2357 0.1 M also determined DNMT1 efflux from, and p300 influx to, the nucleus. Moreover, 0.1 M ITF2357 determined local H4 acetylation and release of DNMT1, HDAC1 and AML1/ETO, paralleled by recruitment of p300 to the IL-3 gene promoter. ITF2357 treatment, however, did not induce re-expression of IL-3 gene. Accordingly, the methylation level of IL-3 promoter, as well as of several other genes, was unmodified. In conclusion, ITF2357 emerged as an anti-leukaemic agent very potent on AML cells, and on AML1/ETO-positive cells in particular. More relevantly, clearly emerged from our results that ITF2357 could be an ideal agent to treat AML subtypes presenting AML1/ETO fusion protein which determine HDAC involvement in leukaemogenesis.