Combining the differentiating effect of panobinostat with the apoptotic effect of arsenic trioxide leads to significant survival benefit in a model of t(8;21) acute myeloid leukemia

Clinical Epigenetics

Ricky W Johnstone²  Johannes Zuber⁴  Peter Atadja⁵  Kym L Stanley¹  Eva Vidacs¹  Michael Bots³  Jessica M Salmon² 

[1] Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne 3002, VIC, Australia;The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia;Laboratory of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands;Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, Vienna, A-1030, Austria;China Novartis Institutes for Biomedical Research, No. 2 BoYun Road, Pudong 201203, Shanghai, China

关键词: Therapy;    Apoptosis;    Differentiation;    Arsenic trioxide;    Histone deacetylase inhibitor;    AML;   

Others  :  1092752
DOI  :  10.1186/s13148-014-0034-4

 received in 2014-08-24, accepted in 2014-12-09,  发布年份 2015

【 摘 要 】

Background

One of the most frequently found abnormalities in acute myeloid leukemia (AML) is the t(8;21)(q22;q22) translocation, which is seen in around 15% of patients. This translocation results in the production of the AML1/ETO (A/E) fusion protein and commonly involves cooperating activating mutations of RAS. AE9a encodes a C-terminally truncated A/E protein of 575 amino acids that retains the ability to recruit histone deacetylases (HDACs). Expression of AE9a leads to rapid development of leukemia in experimental mouse systems. We have recently shown that treatment of mice bearing A/E9a;Nras^G12D tumors with the histone deacetylase inhibitor (HDACi) panobinostat leads to degradation of the A/E9a fusion protein, cell cycle arrest, differentiation of AML blasts into mature granulocytes and prolonged survival. Herein, we sought to enhance this therapeutic effect.

Findings

Combined treatment of mice bearing A/E9a;Nras^G12D leukemias with panobinostat and arsenic trioxide (ATO) resulted in a significant survival advantage compared to mice treated with either agent alone. Moreover, some of the mice treated with the panobinostat/ATO combination showed complete tumor responses and remained in remission for over 220 days. Panobinostat caused differentiation of A/E9a;Nras^G12D cells while ATO induced apoptosis of the leukemic cells, an effect that was enhanced following co-treatment with panobinostat.

Conclusions

Our results indicate that leukemic blast differentiation mediated by panobinostat combined with induction of apoptosis by ATO could be therapeutically beneficial and should be considered for patients with t(8;21) AML.

【 授权许可】

   
2015 Salmon et al.; licensee BioMed Central.

【 图 表 】

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