Poster Presentation 27th Lorne Cancer Conference 2015

miRNA-124 Expression Correlates with Epigenetic Treatment Response in Myeloid Malignancies (#215)

Hongbin Liu 1 2 , Phillip R Pattie 1 2 , Andrew Spencer 2 3 , Anthony 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 treatment (EGT) for myelodysplastic syndrome (MDS) patients improves survival1. However, not all patients respond and treatment regimes are often lengthy with responses frequently only observed after several cycles of therapy1. The problematic response to EGT in MDS has generated a significant demand for molecular markers to improve early prediction of response to EGT.

Epigenetic regulation of microRNA (miRNA) expression has recently been implicated in the pathogenesis of MDS. Demonstration of epigenetic silencing of the miRNA-124 promoter in murine MDS studies2 together with significant inhibition of miRNA-124 expression and excessive miRNA124 promoter methylation in MDS patients3 suggests miRNA-124 may not only be implicated in the pathogenesis of MDS but also potentially in the molecular mechanisms associated with response to EGT. Our study aimed to evaluate the effects in vitro and in vivo of EGT on miRNA-124 expression in order to determine the molecular mechanisms associated with response to EGT and potential for identification of novel molecular markers predictive of early response to EGT.

Analysis of miRNA124 expression in HL-60 leukemia cells treated with either the demethylating agent azacytidine (AZA) or the histone deacetylase inhibitor (HDACi) MCT-3 or a combination of these agents demonstrated a significant and synergistic increase in miRNA-124 expression. miRNA-124 expression was analysed in peripheral blood mononuclear cell samples from high risk MDS/AML patients treated with the combination of AZA and the HDACi LBH5894. Early and significant in vivo induction of miRNA-124 expression was identified in patient samples and was also significantly correlated with subsequent clinical and laboratory response to treatment in those patients responding to treatment. Together these observations suggest miRNA-124 is epigenetically regulated in vitro and in vivo and may be a useful molecular marker of early EGT response in patients receiving combination treatment with demethylating agent and HDACi for high risk MDS/AML.

  1. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.Lancet Oncol. 10:223-32 (2009).
  2. Dickstein J, Senyuk V, Premanand K, Laricchia-Robbio L, Xu P, Cattaneo F, Fazzina R, Nucifora G. 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).
  3. 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).
  4. Tan P, Wei A, Mithraprabhu S, Cummings N, Liu HB, Perugini M, Reed K, Avery S, Patil S, Walker P, Mollee P, Grigg A, D'Andrea R, Dear A, Spencer A. Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer J.10;4:e170 (2014).