Distinct Noncoding RNAs and RNA Binding Proteins Associated with High-Risk Pediatric and Adult Acute Myeloid Leukemias Detected by Regulatory Network Analysis

Abstract

Background: Acute myeloid leukemia (AML) is a heterogeneous disease in both children and adults. Although it is well-known that adult and pediatric AMLs are genetically distinct diseases, the driver genes for high-risk pediatric and adult AMLs are still not fully understood. Particularly, the interactions between RNA binding proteins (RBPs) and noncoding RNAs (ncRNAs) for high-risk AMLs have not been explored.

Aim: To identify RBPs and noncoding RNAs (ncRNAs) that are the master regulators of high-risk AML.

Methods: In this manuscript, we identify over 400 upregulated genes in high-risk adult and pediatric AMLs respectively with the expression profiles of TCGA and TARGET cohorts. There are less than 5% genes commonly upregulated in both cohorts, highlighting the genetic differences in adult and childhood AMLs. A novel distance correlation test is proposed for gene regulatory network construction. We build RBP-based regulatory networks with upregulated genes in high-risk adult and pediatric AMLs, separately.

Results: We discover that three RBPs, three snoRNAs, and two circRNAs function together and regulate over 100 upregulated RNA targets in adult AML, whereas two RBPs are associated with 17 long noncoding RNAs (lncRNAs), and all together regulate over 90 upregulated RNA targets in pediatric AML. Of which, two RBPs, MLLT3 and RBPMS, and their circRNA targets, PTK2 and NRIP1, are associated with the overall survival (OS) in adult AML (p ≤ 0.01), whereas two different RBPs, MSI2 and DNMT3B, and 13 (out of 17) associated lncRNAs are prognostically significant in pediatric AML.

Conclusions: Both RBPs and ncRNAs are known to be the major regulators of transcriptional processes. The RBP-ncRNA pairs identified from the regulatory networks will allow better understanding of molecular mechanisms underlying high-risk adult and pediatric AMLs and assist in the development of novel RBPs and ncRNAs based therapeutic strategies.

Keywords: RBPs, adult and pediatric AMLs, distance correlation test, gene regulatory networks, high-risk AMLs, ncRNAs, prognostic markers