MicroRNA patterns associated with clinical prognostic parameters and CNS relapse prediction in pediatric acute leukemia

Hua Zhang, Xue-Qun Luo, Peng Zhang, Li-Bin Huang, Yu-Sheng Zheng, Jun Wu, Hui Zhou, Liang-Hu Qu, Ling Xu, Yue-Qin Chen, Hua Zhang, Xue-Qun Luo, Peng Zhang, Li-Bin Huang, Yu-Sheng Zheng, Jun Wu, Hui Zhou, Liang-Hu Qu, Ling Xu, Yue-Qin Chen

Abstract

Background: Recent 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 findings: A 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/significance: There 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.

Conflict of interest statement

Competing Interests: One of the co-authors, Dr. Peng Zhang who is also affiliated with the Ooparts Corporation in the US, has received reimbursement for traveling to China from Sun Yat-sen University. The Ooparts Corporation is a consultant company, no any business is related with the work in the paper. No active URL for the company.

Figures

Figure 1. Cluster analysis in pediatric ALL…
Figure 1. Cluster analysis in pediatric ALL and AML and miRNA expression in pediatric ALL and AML validated with qRT-PCR using the validation cohort.
(A) The 182 top–ranked differentially expressed miRNAs in pediatric ALL; (B) The 131 top–ranked differentially expressed miRNAs in the French-American-British (FAB) classification of pediatric AML; (C) MiR-100 expression in pediatric ALL and AML validation cohort (p = 0.000); (D) MiR-34a was up-regulated in pediatric ALL validation cohort (p = 0.003); (E) MiR-146a was up-regulated in AML validation cohort (p = 0.046).
Figure 2. MiRNA expressions in AML subtypes…
Figure 2. MiRNA expressions in AML subtypes were validated with qRT-PCR using the validation cohort and miRNA expression pattern associated with CNS relapse.
(A) MiR-335 and miR-126 expressions in AML subtypes using the validation cohort (the p values for miR-126 were p = 0.006 in M1, p = 0.000 in M2 and p = 0.000 in M3, respectively); (B) MiR-125b expression in AML subtypes using the validation cohort (the p values for miR-125 were p = 0.037 in M2, p = 0.000 in M3, p = 0.000 in M4 and p = 0.002 in M5, respectively); (C) MiRNA expression pattern of pediatric ALL associated with or without CNS relapse; (D) MiR-126 (p = 0.005), miR-222 (p = 0.000) and miR-345 (p = 0.000) were confirmed down-regulated in pediatric ALL patients with CNS relapse compared with non-CNS relapse using the validation cohort.
Figure 3. MiRNA expressions associated withz risk…
Figure 3. MiRNA expressions associated withz risk group, response to prednisone and relapse in ALL subtypes.
(A) MiR-182 was highly expressed in IR groups of ALL (p = 0.000) was confirmed by qRT-PCR using the validation cohort; (B) MiRNA expression pattern of pediatric ALL associated with responses to prednisone treatment Pediatric ALL; (C) Differentially expressed miR-18a (p = 0.000) and miR-193a (p = 0.001) in ALL patients with different responses to prednisone treatment were validated by qRT-PCR using the validation cohort; (D)MiRNA expression pattern in the relapse and non-relapse of pediatric ALL. *p

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