MicroRNAs and acute myeloid leukemia: therapeutic implications and emerging concepts

Abstract

Acute myeloid leukemia (AML) is a deadly hematologic malignancy characterized by the uncontrolled growth of immature myeloid cells. Over the past several decades, we have learned a tremendous amount regarding the genetic aberrations that govern disease development in AML. Among these are genes that encode noncoding RNAs, including the microRNA (miRNA) family. miRNAs are evolutionarily conserved small noncoding RNAs that display important physiological effects through their posttranscriptional regulation of messenger RNA targets. Over the past decade, studies have identified miRNAs as playing a role in nearly all aspects of AML disease development, including cellular proliferation, survival, and differentiation. These observations have led to the study of miRNAs as biomarkers of disease, and efforts to therapeutically manipulate miRNAs to improve disease outcome in AML are ongoing. Although much has been learned regarding the importance of miRNAs in AML disease initiation and progression, there are many unanswered questions and emerging facets of miRNA biology that add complexity to their roles in AML. Moving forward, answers to these questions will provide a greater level of understanding of miRNA biology and critical insights into the many translational applications for these small regulatory RNAs in AML.

Figure 1.

Mechanisms of dysregulated miRNA expression in AML. miRNA dysregulation can contribute to the development of AML. Thus far, numerous mechanisms by which miRNAs become dysregulated in AML have been identified, including (1) deletions leading to decreased miRNA expression, (2) improper expression because of close proximity to an oncogenic genomic region created as a result of either a translocation event or overexpression of a neighboring protein-coding gene, (3) copy number amplifications leading to increased miRNA expression, (4) epigenetic alterations affecting miRNA expression, (5) miRNA promoter regions being aberrantly targeted by dysregulated transcription factors or oncoproteins, and (6) dysregulated miRNA processing leading to altered levels of mature miRNAs.

Figure 2.

miRNAs play context-dependent roles in AML. A model for context-dependent effects of a specific miRNA given different transcriptional backgrounds between 2 distinct AML-driver mutations, mutation A and mutation B. Mutation A leads to the transcription of mRNA A, B, and C, whereas mutation B drives the transcription of mRNA X, Y, and Z. All mRNAs have predicted targeting by the example miRNA. The miRNA depicted in mutation A and mutation B is the same hypothetical miRNA.

Figure 3.

Alternate miRNA sources and noncanonical targeting. A schematic depicting the varying sources identified for production of mature miRNAs, including the 5′ or 3′ strand of the traditional miRNA hairpin structure, processing of other noncoding RNAs, such as lncRNAs, small nucleolar RNAs (snoRNAs), miRNAs transcribed from the same gene but having different mature miRNA sequences (isomiRs), and miRNA spliced from introns (miRtrons). Nontraditional miRNA targets beyond the 3′ UTR are also depicted, including promoter regions of protein-coding genes, the 5′ UTR, the RNA coding sequence, and protein.

Figure 4.

Exosomally transferred miRNAs alter leukemic phenotypes. A model depicting the different possibilities of exosomal miRNA transfer in the bone marrow, including (1) transfer from AML blast to normal hematopoietic cells (NHCs), (2) NHC to AML blast, (3) AML blast to AML blast, (4) bone marrow (BM) stromal cells to AML blast, (5) AML blast to BM stromal cells, (6) entrance of extramedullary produced exosomes into the hematopoietic niche, and (7) AML blast-derived exosomes leaving the BM and entering circulation.

Figure 5.

lncRNAs can interfere with miRNA function in AML. A picture depicting the ways lncRNAs can affect miRNA biology in AML, including (1) lncRNAs serving as a source for mature miRNA production, (2) lncRNAs acting as miRNA sponges, binding miRNAs to prevent them from repressing their target mRNAs, and (3) altering miRNA gene transcription.