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Abstract Background MicroRNAs are of special interest in cancer research and hold significant promise as diagnostic and prognostic biomarkers for malignant disease. MiR-362-5p have been found to exert both oncogenic and tumor suppressive effects depending highly on the cellular context. The aim of this study was to determine whether the expression of miR-362-5p can be served as a prognostic factor for patients with cytogentically normal acute myeloid leukemia (CN-AML). Methods We enrolled 224 patients with CN-AML and measured the expression of miR-362-5p by quantitative real time PCR analysis. We classified patients into high and low expression based on the median value. The Cox regression analyses were carried out to assess the prognostic significance of miR-362-5p expression in the context of the well-established predictors. Additionally, microRNA expression profiling were conducted to identify the biological insights between high and low group. Results High expressers had older age. High expressers obtained shorter overall survival in the univariate analysis. The independent prognostic value of miR-362-5p remained in the context of the well-established clinical and cytogenetic predictors. Moreover, the prognostic value of miR-362-5p was also validated in an independent cohort of CN-AML. Notably, numerous oncomiRs were also high expressed in high miR-362-5p group. Conclusion High miR-362-5p expression was associated with poorer overall survival implicating the oncogenic function in AML development.

The effect of time from diagnosis to treatment (TDT) on overall survival of patients with acute myeloid leukemia (AML) remains obscure. Furthermore, whether chemotherapy delay impacts overall survival (OS) of patients with a special molecular subtype has not been investigated. Here, we enrolled 364 cases of AML to assess the effect of TDT on OS by fractional polynomial regression in the context of clinical parameters and genes of FLT3ITD, NPM1, CEBPA, DNMT3a, and IDH1/2 mutations. Results of the current study show IDH1/2 mutations are associated with older age, M0 morphology, an intermediate cytogenetic risk group, and NPM1 mutations. TDT associates with OS for AML patients in a nonlinear pattern with a J shape. Moreover, adverse effect of delayed treatment on OS was observed in patients with IDH1/2 mutations, but not in those with IDH1/2 wildtype. Therefore, initiating chemotherapy as soon as possible after diagnosis might be a potential strategy to improve OS in AML patients with IDH1/2 mutations.

Cell differentiation agent II (CDA-II) is a DNA methyltransferase inhibitor isolated from healthy human urine. In the present study, the antitumor activity of CDA-II on human multiple myeloma (MM) cell lines via the mitochondrial pathway was first revealed. The human MM cell lines were exposed to CDA-II. Cytotoxicity, caspase activation, apoptosis and the effects on the mitochondrial pathway were assessed. CDA-II was capable of decreasing the depolarized mitochondrial membranes and activating caspase 3 and 9 and poly (ADP ribose) polymerase in MM cells treated with CDA-II. CDA-II induced caspase dependent cell death accompanied by a significant decrease in X-linked inhibitor of apoptosis protein (XIAP), survivin and Mcl 1 levels. The caspase 3 inhibitor, Z DEVD FMK, inhibited CDA-II induced apoptosis. CDA-II potently increased the Bax levels, decreased the Bcl 2/Bax ratio and decreased the expression of the downstream targets of NF κB. In conclusion, the results of the present study demonstrated that CDA-II treatment leads to the inhibition of p65 nuclear localization and potently induces caspase dependent apoptosis in MM cells mediated through the mitochondrial pathway at low nanomolar concentrations. These results indicate that CDA-II is a novel inhibitor of NF κB activity, with notable antimyeloma efficacy. This study provides a rationale for the clinical investigation of CDA-II in human MM. [ABSTRACT FROM AUTHOR]

The 2-hydroxyglutarate (2-HG) has been reported to result from mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes and to function as an "oncometabolite." To evaluate the clinical significance of serum 2-HG levels in hematologic malignancies, acute myeloid leukemia (AML) in particular, we analyzed this metabolite in distinct types of human leukemia and lymphoma and established the range of serum 2-HG in appropriate normal control individuals by using gas chromatograph-time-of-flight mass spectrometry. Aberrant serum 2-HG pattern was detected in the multicenter group of AML, with 62 of 367 (17%) patients having 2-HG levels above the cutoff value (2.01, log2-transformed from 4.03 µg/mL). IDH1/2 mutations occurred in 27 of 31 (87%) AML cases with very high 2-HG, but were observed only in 9 of 31 (29%) patients with moderately high 2-HG, suggesting other genetic or biochemical events may exist in causing 2-HG elevation. Indeed, glutamine-related metabolites exhibited a pattern in favor of 2-HG synthesis in the high 2-HG group. In AML patients with cytogenetically normal AML (n = 234), high 2-HG represented a negative prognostic factor in both overall survival and event-free survival. Univariate and multivariate analyses confirmed high serum 2-HG as a strong prognostic predictor independent of other clinical and molecular features. We also demonstrated distinct gene-expression/DNA methylation profiles in AML blasts with high 2-HG compared with those with normal ones, supporting a role that 2-HG plays in leukemogenesis. [ABSTRACT FROM AUTHOR]