MicroRNA Dysregulation in Acute Myeloid Leukemia

Abstract

In the article that accompanies this editorial, Marcucci et al present data on the clinical significance of the overexpression of miR-155 in patients with cytogenetically normal acute myeloid leukemia (CN-AML). miR-155 is a microRNA that is dysregulated in aggressive lymphomas, in the aggressive form of CLL, and in some solid malignancies such as lung, breast, and colorectal cancer. miR-155 has been shown to inhibit expression of tumor suppressors and genes involved in DNA repair. Interestingly, dysregulation of miR-155 in B cells of mice causes acute lymphoblastic leukemia and high-grade lymphomas. The authors carried out mRNA and microRNA profiling by using microarrays and measured the expression of the transcripts of the miR-155 gene by nCounter technology (NanoString, Seattle, WA), a sensitive amplification independent method. They investigated CN-AML patients, including 153 younger ( 60 years) and 210 older ( 60 years) patients, with untreated primary CN-AML who received intensive first-line therapy on CALGB trials and had diagnostic bone marrow or blood specimens available for molecular analyses. The results of their careful analysis show that miR-155 expression levels constitute an independent prognostic factor in patients with CN-AML. While higher miR-155 expression levels had a negative impact on the outcome of younger and older patients, higher miR-155 expression was associated with lower complete response (CR) rate, and shorter disease-free survival (DFS) and overall survival (OS) in younger patients. Higher miR-155 expression level was associated only with lower CR and shorter OS in older patients. Such findings could be related to biologic differences and differences in the intensity of consolidation therapy. At diagnosis, high miR-155 levels occurred more frequently in patients with AML who were FLT3-ITD positive, RUNX1-mutated, WT1 mutated, and had high ERG and BAALC expressors, and less frequently in CEBPA-mutated, IDH2-mutated and FLT3-tyrosine kinase–positive patients with AML. Thus, higher miR-155 levels associate with unfavorable prognosticators and predict worse CR and survival in both young and old patients. In multivariable analysis, patients with CN-AML with higher levels of miR-155 were approximately 50% less likely to achieve CR. Higher miR-155 expressors had also a 60% increased risk of death and were independent of FLT3-ITD. An international panel of experts on CN-AML on behalf of the European LeukemiaNet recommended a modified classification of patients with CN-AML. When the authors analyzed the prognostic significance of miR-155 in patients classified in the ENL favorable genetic group, younger patients with high miR-155 expression had significantly lower CR rates and shorter event-free survival and OS than patients with low expression, respectively. These correlations were not found with any other microRNA. This is the first clinical study, to our knowledge, where expression of miR-155 was evaluated by using the nCounter technology to understand how different expression levels of miR-155 may affect the aggressiveness of the disease, outcome, and response to treatment of patients with CN-AML. The results indicate that high levels of expression of miR-155 positively correlate with antiapoptotic activity and NF B activation. Although dysregulation of miR-155 in B cells and myeloid cells has been shown to be associated to aggressive malignancy and myeloproliferative disorders respectively in mouse models, the present study tries to assess the role of the dysregulation of this microRNA in patients with CN-AML. Their results support the hypothesis that miR-155 expression contributes to different degrees of aggressiveness in leukemia by affecting proliferation and survival of the leukemia cells. A conclusion of this study, as clearly indicated by the authors, is that if we want to have an effect in the treatment of this group of AML patients, we should try to revert miR-155 overexpression, for example, by using anti-miR-155 oligonucleotides or by inhibiting the pathways that regulate the levels of miR-155 expression. In addition, given that miR-155 is relatively easy to measure at diagnosis, we should consider the levels of miR-155 as a biomarker for risk stratification and guidance for treatment.