Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells

Barbetti, Valentina; Gozzini, Antonella; Rovida, Elisabetta; Morandi, Andrea; Spinelli, Elena; Fossati, Gianluca; Mascagni, Paolo; Lübbert, Michael; Sbarba, Persio Dello; Santini, Valeria

doi:10.1038/sj.onc.1210820

Cited by 45 publications

(43 citation statements)

References 33 publications

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“…We have previously demonstrated a selective anti-leukemic activity of the HDAC inhibitor givinostat (ITF2357) on AML1/ETO-positive cells 14 . This cellular and molecular model is particularly intriguing because it may constitute a selective target for epigenetic therapy.…”

Section: Discussionmentioning

confidence: 99%

Redistribution of H3K27me3 and acetylated histone H4 upon exposure to azacitidine and decitabine results in de-repression of the AML1/ETO target geneIL3

et al. 2013

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Human acute myeloid leukemia is characterized by a block in maturation caused by genetic and epigenetic alterations. We studied the effects of low concentrations of the DNA methyltransferase (DNMT) inhibitors 5-azacitidine and decitabine on apoptosis and on chromatin remodeling in an AML1/ETO inducible model of human AML. While both DNMT inhibitors induced apoptosis, only azacitidine did so via caspase activation, possibly through its exclusive non-DNA depending effects. We evaluated histone marks for permissive chromatin, H3K4me3, and acetylated histone H4, and for non-permissive chromatin, H3K9me2, and H3K27me3, at the promoter of the IL3 gene, which is under the direct control of AML1/ETO and is critical for myeloid maturation. We observed that low concentrations of DNMT inhibitors induced a loss of H3K27me3 and gain of acetylated histone H4 at the IL3 promoter exclusively in AML1/ETO-positive cells, which was associated with transcriptional reactivation of the IL3 gene.

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Section: Discussionmentioning

confidence: 99%

Redistribution of H3K27me3 and acetylated histone H4 upon exposure to azacitidine and decitabine results in de-repression of the AML1/ETO target geneIL3

et al. 2013

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“…A better understanding of oncofusion proteins as mediators of epigenetically silenced states also drives the search for 'targeted' therapies that specifically antagonize their repressive effects. Examples for clinical models include treatment of PML/RARa transgenic mice with HDAC inhibitors, as well as AML1/ETOexpressing cell lines and transgenic cell models (Yang et al, 2007;Barbetti et al, 2008). Recently, the group of Clara Nervi has shown that the hypermethylated state of the RARb2 promoter CpG island can be converted to a demethylated, transcriptionally active promoter by treatment with the DNA-demethylating agent 5-azacytidine (Fazi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

et al. 2011

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The chromosomal translocation (8;21) fuses the hematopoietic transcription factor AML1 (RUNX1) with ETO (RUNX1T1, MTG8), resulting in the leukemia-specific chimeric protein AML1/ETO. This fusion protein has been implicated in epigenetic silencing, recruiting histone deacetylases (HDACs) and DNA methyltransferases to target promoters. Previously, we have identified a novel in vivo AML1/ETO target gene, LAT2 (NTAL/LAB/ WBSCR5), which is involved in FceR I, c-Kit, B-cell and T-cell receptor signalling. We have now addressed the molecular mechanisms of AML1/ETO-mediated LAT2 repression. In Kasumi-1 cells, where AML1/ETO bound to the LAT2 gene, small interfering RNA (siRNA)-mediated AML1/ETO depletion caused upregulation of LAT2, suggesting a possible direct mechanism of repression. Expression of AML1/ETO was associated with a decrease in acetylation of histones H3, H3K9 and H4, and an increase in H3K9 and H3K27 trimethylation. The class I-specific HDAC inhibitors entinostat (MS-275) and mocetinostat (MGCD0103) induced LAT2 expression specifically in AML1/ETO-expressing cells, resulting in induction of several activating histone marks on the LAT2 gene, including trimethylation of histone H3K4. The combination of entinostat and decitabine increased acetylation of histones H3 and H4, as well as LAT2 mRNA expression, in an at least additive fashion. In conclusion, several repressive histone modifications mark the LAT2 gene in the presence of AML1/ETO, and LAT2 gene derepression is achieved by pharmacological inhibition of HDACs.

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“…73-75 Givinostat inhibits the growth of JAK2 V617F cell lines as well as primary hematopoietic cells from patients with PV and ET. 76 In a phase IIA study, 12 patients with PV and 1 with ET received givinostat orally at a starting dose of 50 mg twice daily for 24 weeks.…”

Section: Novel Agentsmentioning

confidence: 99%

New Therapeutic Approaches in Polycythemia Vera

Falchi

Newberry

Verstovšek

2015

Clinical Lymphoma Myeloma and Leukemia

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Polycytemia vera (PV) is one of the three Philadelphia-negative myeloproliferative neoplasms. Clinically, PV is an indolent disease but its course can be complicated by arterial and venous vascular accidents, evolution to myelofibrosis or leukemic transformation. Treatment of PV is, therefore, aimed at preventing such acute complications. The cornerstone of therapy of low-risk patients remains strict control of cardiovascular risk factors, the use of phlebotomy and low dose aspirin. Higher risk patients should also receive cytoreductive treatments. Hydroxyurea and interferon-α represent standard first-line options for newly diagnosed high-risk PV patients. Recommendations for patients who fail these therapies are less clearly defined. The discovery of a mutation in the Janus kinase 2 gene (V617F) in almost all cases of PV has prompted the development of molecularly targeted agents for the treatment of these patients. In this review we will discuss key clinical aspects, the current therapeutic armamentarium and data on the use of novel agents in patients with PV.

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Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells

Cited by 45 publications

References 33 publications

Redistribution of H3K27me3 and acetylated histone H4 upon exposure to azacitidine and decitabine results in de-repression of the AML1/ETO target geneIL3

Redistribution of H3K27me3 and acetylated histone H4 upon exposure to azacitidine and decitabine results in de-repression of the AML1/ETO target geneIL3

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

New Therapeutic Approaches in Polycythemia Vera

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