Clinical significance of microRNAs in chronic and acute human leukemia

Yeh et al. Molecular Cancer (2016) 15:37 DOI 10.1186/s12943-016-0518-2 REVIEW Open Access Clinical significance of microRNAs in chronic and acute human leukemia Chien-Hung Yeh†, Ramona Moles† and Christophe Nicot* Abstract Small non-coding microRNAs (miRNAs) are epigenetic regulators that target specific cellular mRNA to modulate gene expression patterns and cellular signaling pathways. miRNAs are involved in a wide range of biological processes and are frequently deregulated in human cancers. Numerous miRNAs promote tumorigenesis and cancer progression by enhancing tumor growth, angiogenesis, invasion and immune evasion, while others have tumor suppressive effects (Hayes, et al., Trends Mol Med 20(8): 460–9, 2014; Stahlhut and Slack, Genome Med 5 (12): 111, 2013). The expression profile of cancer miRNAs can be used to predict patient prognosis and clinical response to treatment (Bouchie, Nat Biotechnol 31(7): 577, 2013). The majority of miRNAs are intracellular localized, however circulating miRNAs have been detected in various body fluids and represent new biomarkers of solid and hematologic cancers (Fabris and Calin, Mol Oncol 10(3):503–8, 2016; Allegra, et al., Int J Oncol 41(6): 1897–912, 2012). This review describes the clinical relevance of miRNAs, lncRNAs and snoRNAs in the diagnosis, prognosis and treatment response in patients with chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) and acute adult T-cell leukemia (ATL). Background Chronic lymphocytic leukemia (CLL) CLL is characterized by slow growth and the accumulation of incompetent CD5+, CD19+ and CD23+ B lymphocytes in blood, marrow, and other lymphoid tissues. This disease can be distinguished into aggressive and indolent subtypes with deletion of chromosome 13q14 being the most common genetic alteration found at diagnosis. miRNA signature in CLL The miR-15/16 cluster, miR-34b/c, miR-29, miR-181b, miR-17/92, miR-150, and miR-155 represent the most frequently deregulated miRNAs reported in CLL, and these microRNAs have been associated with disease progression, prognosis, and drug resistance [1] (Table 1). Nearly two-thirds of CLL cases presented a down-regulation of miR-15a/16-1 expression. In fact, miR-15a and miR-161 are located in the locus 13q14.3, a genomic region frequently deleted in CLL patient samples [2]. However, additional mechanisms, such as overexpression of histone deacetylases (HDACs), also down-regulateed expression of * Correspondence: † Equal contributors Department of Pathology, Center for Viral Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City KS 66160, USA miR-15 and miR-16 [3]. An inverse correlation between miR-15a/16-1 and BCL2 expression has been reported in CLL, and inhibition of this microRNA expression in leukemic cell lines led to increased BCL2 expression and resistance to apoptotic signals. Comparative microarray analysis in CLL patients with high or low levels of miR-15a/16-1 identified a gene signature that contains the anti-apoptotic BCL2 family member MCL-1, which was associated with B-CLL cell survival and chemotherapy resistance [4–6]. Down-regulated miR-15a and miR-16-1 in CLL patients has been associated with a good prognosis, consistent with previous reports that correlated 13q14.3 deletions with a favorable course of CLL [7]. The miR-29 family, which includes miR-29a, miR-29b and miR-29c, was also significantly down-regulated in a subset of CLL patients and was associated with an unfavorable prognosis. miR-29b targets DNA methyltransferase (DNMT) isoforms and inhibition of miR-29b expression may lead to hypermethylation and epigenetic silencing of several tumor suppressors [7] (Table 2). In addition, evidence showed that miR-29 targets the oncogene T-cell leukemia 1 gene, TCL1A, which was overexpressed in patients with unmutated immunoglobulin heavy chain variable regions (IgVH) and involved in translocations and inversions characteristic of mature T-cell prolymphocytic © 2016 Yeh et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yeh et al. Molecular Cancer (2016) 15:37 Page 2 of 16 Table 1 microRNAs deregulated and associated with clinical outcome in human Leukemia The figure represents a summary of miRNAs associated with a poor or a favorable prognosis in CLL, CML, ALL, AML and ATL. Highlighted in red and green are the miRNAs that are found most frequently associated with an unfavorable or favorable outcome, respectively, across different human leukemias leukemia (PLL). Transgenic mice that overexpressed TCL1 in B cells displayed a similar phenotype to aggressive forms of human CLL [7]. Another genomic region frequently deleted in CLL patients was found in the 11q region where a miR-34 cluster is located. In fact, down-regulation of miR-34a in CLL has been associated with p53 inactivation, impaired DNA damage response, and apoptosis resistance [8–10]. Since miR-34a also inhibited E2F1 and B-Myb [11], loss of miR-34a expression may increase tumor cell proliferation. In contrast, the miR-17/92 polycistronic microRNA cluster was overexpressed in several lymphoid malignancies and inhibits the expression of the pro-apoptotic factor Bim and the tumor suppressor PTEN [12]. Activation of STAT3-induced IL-6 in tumor cells stimulates the expression of miR-17 and miR-19a, resulting in lower expression of TLR7 and TNFα. In addition, CLL patient cells expressing zeta-chainassociated protein 70 kDa (ZAP-70) have demonstrated significantly lower levels of miR-150 expression when compared with ZAP-70-negative CLL cells. In CLL cells miR-150 targeted forkhead box P1 (FOXP1) and GRB2associated binding protein 1 (GAB1), thereby reducing B-cell receptor signaling [13]. Another STAT3-activated microRNA, miR-155 [14], has been overexpressed in cells and in circulating microvesicles in CLL samples [14]. Induction of the oncomiR-155 in the plasma of CLL patients correlates with poor response to treatment and disease progression and, consistent with this, patients who achieved complete remission presented low levels of miR-155 in the plasma [1]. In addition, the expression of miR-155 was increased with disease progression from monoclonal B-cell lymphocytosis (MBL) to CLL and was higher in MBL and CLL than normal controls [15]. Given this, high expression of miR-155 was associated with a poor clinical prognosis in CLL [16, 1 (...truncated)