Poster Presentation 28th Lorne Cancer Conference 2016

Induction of miRNA124 Correlates with Inhibition of CDK4, CDK6 and EZH2 Expression and Epigenetic Treatment Response in Myeloid Malignancies (#201)

Hongbin Liu 1 2 , Phillip R Pattie 1 2 , Andrew Spencer 2 3 , Anthony E Dear 1 2
  1. Medicine, Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia
  2. Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia
  3. Haematology, Alfred Hospital, Melbourne, Victoria, Australia

Epigenetic regulation of microRNA (miRNA) expression has recently been implicated in the pathogenesis of MDS1,2. Particular interest has focused on miRNA124 expression, inhibited in MDS due to promoter hypermethylation and recently demonstrated to be upregulated in response to single and combined epigenetic treatment (EGT)3,4. These observations suggest miRNA124 is implicated in the therapeutic molecular response to EGT and is a potential biomarker of early EGT response in MDS.

Our ongoing studies aimed to evaluate the in vitro and in vivo effects of EGT on known targets of miRNA124 expression including CDK4, CDK6 and EZH2 in order to further characterise the molecular mechanisms associated with early up regulation of miRNA-124 expression and response to EGT.

Analysis of CDK4, CDK6 and EZH2 mRNA expression in HL-60 leukemia cells treated with either the demethylating agent azacytidine (AZA) or the histone deacetylase inhibitor (HDACi) LBH-589 or a combination of these agents demonstrated significant inhibition of CDK4, CDK6 and EZH2 expression. CDK4, CDK6 and EZH2 mRNA expression was also analysed in peripheral blood mononuclear cell samples from high risk MDS/AML patients treated with the combination of AZA and LBH5895. Early and significant in vivo inhibition of CDK4 and CDK6 mRNA expression and a trend to inhibition of EZH2 was identified in patient samples and was also significantly correlated with subsequent clinical and laboratory response to EGT.

Together these observations suggest that in vitro and in vivo expression of CDK4, CDK6 and potentially EZH2, the downstream targets of EGT-induced miRNA124, are inhibited in response to EGT providing a potential molecular mechanism for the miRNA124-mediated response to EGT therapy in patients receiving combination treatment with a demethylating agent and HDACi for high risk MDS/AML.

  1. Dickstein J et al. Methylation and silencing of miRNA-124 by EVI1 and self-renewal exhaustion of hematopoietic stem cells in murine myelodysplastic syndrome. Proc Natl Acad Sci U S A 107:9783-8 (2010).
  2. Xia Q, Hu J, Meng YS. Abnormal expression of microRNA-124 in patients with leukemia or myelodysplastic syndrome and its significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 20:358-61 (2012).
  3. Castoro R, Saraf A, Watanabe Y, et al. MicroRNA 124 and its role in response to epigenetic therapy in acute myelogenous leukemia and myelodysplastic syndrome. Cancer Research. 68(9 Supplement): LB-253 (2008).
  4. Liu HB, Pattie PR, Spencer A, Dear AE. Induction of miRNA124 expression correlates with epigenetic treatment response in myeloid malignancies. In Proceedings, Lorne Cancer Conference, Melbourne, Victoria, Australia, Feb 12th-14th (2015).
  5. Tan P, et al. Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer J.10;4:e170 (2014).