Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells.
We analysed the in vitro effects of a new hydroxamate derivative, ITF2357, on AML cells. ITF2357 potently induced histone acetylation. ITF2357 0.1 microM 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 microM ITF2357. Apoptosis was induced by 0.1 microM 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 microM ITF2357 induced AML1/ETO degradation through a caspase-dependent mechanism. ITF2357 0.1 microM also determined DNMT1 efflux from, and p300 influx to, the nucleus. Moreover, 0.1 microM 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.
Barbetti
V
V
Dipartimento di Patologia e Oncologia Sperimentali, Università degli Studi di Firenze, Firenze, Italy.
Gozzini
A
A
Rovida
E
E
Morandi
A
A
Spinelli
E
E
Fossati
G
G
Mascagni
P
P
Lübbert
M
M
Dello Sbarba
P
P
Santini
V
V
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000096:biosynthesis*; D020298:U937 Cells
D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; C502418:givinostat hydrochloride