RUNX1: A microRNA hub in normal and malignant hematopoiesis

Abstract

Hematopoietic development is orchestrated by gene regulatory networks that progressively induce lineage-specific transcriptional programs. To guarantee the appropriate level of complexity, flexibility, and robustness, these networks rely on transcriptional and post-transcriptional circuits involving both transcription factors (TFs) and microRNAs (miRNAs). The focus of this review is on RUNX1 (AML1), a master hematopoietic transcription factor which is at the center of miRNA circuits necessary for both embryonic and post-natal hematopoiesis. Interference with components of these circuits can perturb RUNX1-controlled coding and non-coding transcriptional programs in leukemia.

Figure 1

(a) RUNX1 is a hub of miRNAs targeting RUNX1 and miRNAs targeted by RUNX1. A number of miRNAs (>60 predicted by Targetscan, of which shown are only the ones experimentally validated) can inhibit RUNX1 protein expression by targeting the 3′UTR of RUNX1 mRNA. RUNX1 is predicted to target more than 200 miRNAs (shown are only the ones experimentally validated) and either repress or activate their transcription. Some miRNAs, such as miR-17 and miR-27, in turn can target RUNX1 in a feedback loop (dotted arrow). (b) Examples of possible RUNX1-miRNA feedback loops involved in megakaryocytic, monocytic, and granulocytic differentiation. In the latter case, RUNX1 may control miR-27 transcription indirectly, via CCAAT/enhancer-binding protein alpha (CEBPA) (dotted arrow).

Figure 2

Several factors can potentially disrupt RUNX1-miRNA circuits, including deregulation of RUNX1-targeting miRNAs. RUNX1 function has been shown to be deregulated by altered RUNX1 dosage (haploinsufficiency), point mutations, or chromosomal rearrangements (e.g., t(8;21), producing RUNX1-ETO). In addition, RUNX1 expression could be affected by deregulation of miRNAs targeting RUNX1. The impairment of RUNX1 function would lead to deregulation of RUNX1-target genes, including miRNAs (in red are shown the RUNX1-target miRNAs known to be repressed by RUNX1-ETO, while in black are shown other established RUNX1-target miRNAs). Deregulation of miR-223 and miR-222-221 by RUNX1-ETO is known to affect their targets, NF1A and KIT. Since RUNX1 can target, and be targeted by, the same miRNAs, deregulation of wild type RUNX1 may be reinforced or weakened through a feedback loop (dotted arrow). Similarly, RUNX1 function could be affected by impairment of its heterodimeric partner CBFB, which could be subjected to miRNA-mediated deregulation in addition to known chromosomal rearrangements.