The Role of MicroRNA in Paediatric Acute Lymphoblastic Leukaemia: Challenges for Diagnosis and Therapy

Abstract

Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Although the overall survival of children with ALL is now more than 90%, leukaemia remains one of the leading causes of death from disease. In developed countries, the overall survival of patients with ALL has increased to more than 80%; however, those children cured from ALL still show a significant risk of short- and long-term complications as a consequence of their treatment. Accordingly, there is a need not only to develop new methods of diagnosis and prognosis but also to provide patients with less toxic therapies. MicroRNAs (miRNAs) are small ribonucleic acids (RNA), usually without coding potential, that regulate gene expression by directing their target messenger RNAs (mRNAs) for degradation or translational suppression. In paediatric ALL, several miRNAs have been observed to be overexpressed or underexpressed in patient cohorts compared to healthy individuals, while numerous studies have identified specific miRNAs that can be used as biomarkers to diagnose ALL, classify it into subgroups, and predict prognosis. Likewise, a variety of miRNAs identify as candidate targets for treatment, although there are numerous obstacles to overcome before their clinical use in patients. Here, we summarise the roles played by different miRNAs in childhood leukaemia, focussing primarily on their use as diagnostic tools and potential therapeutic targets, as well as a role in predicting treatment outcome. Finally, we discuss the potential roles of miRNA in immunotherapy and the novel contributions made by gut miRNAs to regulation of the host microbiome.

Figure 1

The functional mechanism of miRNA in posttranscriptional regulation of gene expression. miRNAs function to regulate the expression of genes by binding to the 3′ untranslated regions of their target messenger RNAs (mRNAs). miRNAs downregulate expression through acceleration of the degradation of mRNA (perfect complementarity) or by inhibition of its translation (imperfect complementarity).

Figure 2

Major recurrent chromosome aberrations of childhood BCP-ALL. Hyperdiploidy and the ETV6-RUNX1 translocation constitute the major subgroups of BCP-ALL and are associated with favourable clinical outcome. The t(1;19) and “B-Others” subgroups are associated with intermediate risk and the remaining subgroups are deemed poor risk.

Figure 3

A top-ten discriminative miRNA set for the main leukaemia subgroups. The subtypes display a unique discriminating miRNA (except where overlap is shown) that distinguishes each subgroup from each other [25].

Figure 4

Potential applications of miRNA as a diagnostic and prognostic tool in paediatric ALL. The figure summarises those miRNAs that are either upregulated or downregulated in the various subsets of ALL and their potential use as a tool for its diagnosis and prognosis.

Figure 5

Potential applications of miRNAs as biomarkers of treatment response and toxicity in paediatric ALL. The figure summarises those miRNAs that are either upregulated or downregulated in the various subsets of ALL during therapy. Their potential use as a tool for treatment or marking treatment response is discussed in the text.