Role of microRNA dysregulation in childhood acute leukemias: Diagnostics, monitoring and therapeutics: A comprehensive review

Abstract

MicroRNAs (miRNAs) are short noncoding RNAs that regulate the expression of genes by sequence-specific binding to mRNA to either promote or block its translation; they can also act as tumor suppressors (e.g., let-7b, miR-29a, miR-99, mir-100, miR-155, and miR-181) and/or oncogenes (e.g., miR-29a, miR-125b, miR-143-p3, mir-155, miR-181, miR-183, miR-196b, and miR-223) in childhood acute leukemia (AL). Differentially expressed miRNAs are important factors associated with the initiation and progression of AL. As shown in many studies, they can be used as noninvasive diagnostic and prognostic biomarkers, which are useful in monitoring early stages of AL development or during therapy (e.g., miR-125b, miR-146b, miR-181c, and miR-4786), accurate classification of different cellular or molecular AL subgroups (e.g., let-7b, miR-98, miR-100, miR-128b, and miR-223), and identification and development of new therapeutic agents (e.g., mir-10, miR-125b, miR-203, miR-210, miR-335). Specific miRNA patterns have also been described for commonly used AL therapy drugs (e.g., miR-125b and miR-223 for doxorubicin, miR-335 and miR-1208 for prednisolone, and miR-203 for imatinib), uncovering miRNAs that are associated with treatment response. In the current review, the role of miRNAs in the development, progression, and therapy monitoring of pediatric ALs will be presented and discussed.

Keywords: Acute leukemia; Acute lymphoblastic leukemia; Acute myeloid leukemia; Biomarker; Classification; Drug resistance; MiRNome, MicroRNA; Prognosis.

Figure 1

Examples of microRNAs that may exert contrasting oncogenic/tumor-suppressive effects on tumor-modifying extrinsic factors and the leukemic cells themselves (modified from Svoronos et al[19], with the permission of the author). Green arrows, positive regulation; orange arrows, negative regulation; blue arrows, either positive or negative regulation. A narrow extension directly from a microRNA to the central leukemic cell refers to promotion/inhibition of leukemic cell progression/survival through the microRNA’s direct regulation of leukemic cell–endogenous mRNAs.

Figure 2

A top ten discriminative microRNA set for the main acute lymphoblastic leukemia subgroups. The subtypes display a unique discriminating microRNA (except where overlap is shown) that distinguishes each subgroup from each other (modified from Grobbelaar et al[3], with the permission of the author). ALL: Acute lymphoblastic leukemia.

Figure 3

A top ten discriminative microRNA set for the main acute myeloid leukemia subgroups. The subtypes display a unique discriminating microRNA (except where overlap is shown) that distinguishes each subgroup from each other (based on data from Trino et al[69]). AML: Acute myeloid leukemia.

Figure 4

Possible roles of microRNAs in the diagnosis and prognosis of childhood acute lymphoblastic leukemia (modified from Grobbelaar et al[3], with the permission of the author). ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia.

Figure 5

Schematic strategy for the development of new therapeutic protocols to modulate the biological activity of microRNAs. This approach involves several mechanisms of the downregulation of oncomiRNAs or the upregulation/mimicking of oncosuppressor microRNAs (modified from Gokani et al[153], with the permission of the author). miRNAs: microRNAs.