title: 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.
abstract: 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.
  
  
  RESULTS
  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.
authors: 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.
authors: Jessica M
authors: JM
authors: Salmon
authors: Laboratory of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors: Michael
authors: M
authors: Bots
authors: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC Australia.
authors: Eva
authors: E
authors: Vidacs
authors: Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002 VIC Australia.
authors: Kym L
authors: KL
authors: Stanley
authors: China Novartis Institutes for Biomedical Research, No. 2 BoYun Road, Pudong, Shanghai 201203 China.
authors: Peter
authors: P
authors: Atadja
authors: Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
authors: Johannes
authors: J
authors: Zuber
authors: 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.
authors: Ricky W
authors: RW
authors: Johnstone
keywords: AML; Apoptosis; Arsenic trioxide; Differentiation; Histone deacetylase inhibitor; Therapy
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