Abstract
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. The disease is characterized by various cytogenetic and molecular abnormalities with distinct prognoses and gene expression profiles. Emerging evidence has suggested that circulating microRNAs (miRNAs) could serve as noninvasive biomarkers for cancer detection; however, little is known about circulating miRNA profiles in AML patients. In this study, a genome-wide serum miRNA expression analysis was performed using Solexa sequencing for initial screen, followed by validation with real-time PCR assays. The analysis was conducted on training and verification sets of serum samples from 140 newly diagnosed AML patients and 135 normal adult donors. After a two-phase selection and validation process, 6 miRNAs, miR-10a-5p, miR-93-5p, miR-129-5p, miR-155-5p, miR-181b-5p and miR-320d, were found to have significantly different expression levels in AML compared with control serum samples. Furthermore, unsupervised clustering analysis revealed the remarkable ability of the 6-miRNA profile to differentiate between AML patients and normal controls. The areas under the ROC curve for the selected miRNAs ranged from 0.8129 to 0.9531. More importantly, miR-181b-5p levels in serum were significantly associated with overall survival. These data demonstrated that the expression patterns of circulating miRNAs were systematically altered in AML and miR-181b-5p may serve as a predictor for overall survival in AML patients.
Highlights
Acute myeloid leukemia (AML), the most frequent hematological malignancy in adults, is characterized by an accumulation and differentiation arrest of myeloid blasts in the bone marrow and blood that requires immediate treatment to prevent interference with the production of healthy white blood cells in the bone marrow
Solexa Sequencing of Serum miRNAs in AML To select candidate serum miRNAs for AML detection, we performed an initial genome-wide miRNA screening of two pools of serum samples derived from 20 AML patients and 20 matched normal controls by Solexa sequencing (1.0 mL for each sample, 20 mL total for each group)
22 nt and 23 nt RNAs were the dominant small RNAs, each accounting for 12.77% of the total sequences (Fig. 1A), while 22 nt RNAs accounted for 24.64% of the total sequences in the AML library (Fig. 1B)
Summary
Acute myeloid leukemia (AML), the most frequent hematological malignancy in adults, is characterized by an accumulation and differentiation arrest of myeloid blasts in the bone marrow and blood that requires immediate treatment to prevent interference with the production of healthy white blood cells in the bone marrow. The treatment choice and prognosis for newly diagnosed AML patients are based mainly on cytogenetic information, which classifies AML into three risk-based categories: favorable, intermediate, and poor. The favorable prognosis, with a 5-year overall survival (OS) rate of 55%, is associated with AML patients carrying t(16;16), t(15;17) or t(8;21). The intermediate subgroup has a 5-year OS rate ranging between 24 and 42% and includes patients with normal cytogenetics, trisomy 8 or t(9;11). Patients with -5, -5q, -7, -7q, 11q23, t(3;3), t(6;9), t(9;22) or complex cytogenetics are classified as having a poor prognosis, and the 5-year OS rate is only approximately 11% [2]. Despite intensive research in recent decades, the cause of AML is not yet fully understood, and better prognostic indicators and more effective targeted therapies remain elusive
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