MicroRNA Patterns Associated with Clinical Prognostic Parameters and CNS Relapse Prediction in Pediatric Acute Leukemia

Abstract

BackgroundRecent reports have indicated that microRNAs (miRNAs) play a critical role in malignancies, and regulations in the progress of adult leukemia. The role of miRNAs in pediatric leukemia still needs to be established. The purpose of this study was to investigate the aberrantly expressed miRNAs in pediatric acute leukemia and demonstrate miRNA patterns that are pediatric-specific and prognostic parameter-associated.Methodology/Principal FindingsA total of 111 pediatric bone marrow samples, including 99 patients and 12 normal donors, were enrolled in this study. Of those samples, 36 patients and 7 normal samples were used as a test cohort for the evaluation of miRNA profiling; 63 pediatric patients and 5 normal donors were used as a validation cohort to confirm the miRNA differential expression. Pediatric ALL- and AML-specific microRNA expression patterns were identified in this study. The most highly expressed miRNAs in pediatric ALL were miR-34a, miR-128a, miR-128b, and miR-146a, while the highly expressed miRNAs in pediatric AML were miR-100, miR-125b, miR-335, miR-146a, and miR-99a, which are significantly different from those reported for adult CLL and AML. miR-125b and miR-126 may serve as favorable prognosticators for M3 and M2 patients, respectively. Importantly, we identified a “miRNA cascade” associated with central nervous system (CNS) relapse in ALL. Additionally, miRNA patterns associated with prednisone response, specific risk group, and relapse of ALL were also identified.Conclusions/SignificanceThere are existing pediatric-associated and prognostic parameter-associated miRNAs that are independent of cell lineage and could provide therapeutic direction for individual risk-adapted therapy for pediatric leukemia patients.

MicroRNA miR-125b causes leukemia

“…A recent study showed that miR-125b overexpression is associated with the TEL-AML1 fusion protein in ALL patients and it confers a survival advantage in in vitro experiments (23). Furthermore, Zhang et al showed that miR-125b is highly expressed in pediatric AML and in particular in patients with the translocation PML-RARA (26).…”

Clinical and prognostic significance of miR-155 and miR-146a expression levels in formalin-fixed/paraffin-embedded tissue of patients with diffuse large B-cell lymphoma

“…Down-regulation of miR-146a expression by the c-Myc oncogenic transcription factor has been previously observed in human and mouse B-cell lymphomas (30). Recent studies have evaluated the expression levels of miR-146a in acute lymphocytic leukemia and chronic lymphocytic leukemia (31)(32)(33). Their findings imply that miR-146a expression involved in deletion or amplification may be cell type-specific.…”

MiR-125 in normal and malignant hematopoiesis

“…The expression levels varied depending on the methodologies used for expression and controls, but are generally up to 20-fold compared with normal BM. These malignancies include myelodysplastic syndrome involving the del (5q), 39,40 AMLs harboring the AML1/ETO translocation, 41 AMLs associated with the FLT3 mutation, 41 a few cases of chronic myelogenous leukemia, myeoproliferative neoplasms 42 and acute promyelocytic leukemia 43,44 (Table 1). The most investigated hematopoietic malignancy with increased expression of miR-125b is acute megakaryocytic leukemia associated with Down's syndrome (DS).…”