Abstract 1114: Downregulated miR-337-5p is associated with unfavorable features in acute myeloid leukemia and may play a role in modulating the extracellular signal-regulated kinase pathway

We previously revealed that a homozygous deletion T polymorphism in the 3’-untranslated region of the Nucleophosmin (NPM1) gene is associated with adverse outcomes and can independently predict survivals in patients with de novo acute myeloid leukemia (AML). This polymorphism creates an illegitimate binding site for miR-337-5p, which is expressed in different AML subtypes. We speculate that the delT-carrying NPM1 mRNA competes with as yet unidentified oncogenes for miR-337-5p binding, thereby activating their functions in trans and perturbing normal microRNA regulation. In this study, we aim to investigate the clinicopathological and biological significance of miR-337-5p expression in AML. Using real-time RT-PCR, we measured miR-337-5p expression in bone marrow of 156 adult patients with de novo AML excluding acute promyelocytic leukemia. Patients were dichotomized into low and high expression group at the median level for clinicopathological correlations. miR-337-5p levels were significantly reduced in the low expression patient group than the normal controls (n = 27) (P<0.001). Low miR-337-5p expression correlated with higher white blood cell counts (P = 0.024), lactate dehydrogenase levels (P = 0.023), bone marrow blast counts (P = 0.001) and FLT3-ITD (P = 0.0092) mutation. Using TargetScan, DIANA, PITA and miRDB, three putative oncogenes involved in the extracellular signal-regulated kinase (ERK) pathway, namely RAP2B, MAPK1 and WNK1, were consistently indicated as the potential targets of miR-337-5p. Overexpression of miR-337-5p in OCI-AML3 cells, which have barely detectable miR-337-5p levels, downregulated the expression of all targets. Concordantly, luciferase reporter assay confirmed that miR-337-5p bound to the 3’-untranslated region of these targets and inhibited translation. The ERK signaling pathway is frequently activated in AML and confers pro-survival functions. We demonstrated that overexpression of miR-337-5p in OCI-AML3 cells significantly inhibited proliferation in both WST-1 and colony-forming assay. Together, our findings suggested that reduced miR-337-5p is associated with unfavorable clinicopathological and molecular features in AML. Restoration of miR-337-5p suppressed cell proliferation, potentially by downregulation of genes implicated in the mitogenic ERK signaling pathway.

Citation Format: Rosalind Lie, Chi Keung Cheng, Natalie Pui Ha Chan, Rosalina Ip, Nelson Chan, Joyce Cheung, Margaret Ng. Downregulated miR-337-5p is associated with unfavorable features in acute myeloid leukemia and may play a role in modulating the extracellular signal-regulated kinase pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1114.