miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells

Abstract

SummaryTo investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance.

MicroRNAs in Control of Stem Cells in Normal and Malignant Hematopoiesis

“…MiR-152, which potentially regulates Dnmt1, is often heavily methylated in leukemia [90]. MiR-21 [91] and miR-126 [92] both of which play roles in leukemia have been shown to regulate DNMT1 in lymphoid cells [93, 94]. …”

“…Additional studies sought to stratify phenotypic AML LSCs based on their ability to engraft in an immune compromised mouse. A comparison of miRNA expression and the engraftment ability identified miRNAs both positively (miR-99a, miR-125b, miR-155, miR-409, miR-100, miR-320, miR-126, miR-1, miR-542, and miR-15b) and negatively (miR-451, miR-103, miR-200c, miR-423-3p, let7g, miR-30e, miR-26b, miR-140, miR-22, and miR-21) correlate with AML engraftment and LSC activity [92]. These candidate miRNAs provide a perfect list for functional validation as only engraftment and leukemia reconstitution is a reliable way of defining LSCs.…”

“…Overexpression of miR-125b-1 [24], miR-125b-2 [68], miR-155 [80], miR-126 [92] results in leukemia phenotype and all of these miRNAs are capable of regulating enzymes which control DNA methylation as discussed previously. The best-studied miRNA in human AML LSCs is miR-126, whose high expression in leukemia specimens correlates with AML survival [92]. However, opposite to its role in human HSCs discussed earlier, this same miRNA enhances LSC self-renewal and prevents differentiation in vivo .…”

Umbilical Cord Blood Hematopoietic Stem and Progenitor Cell Expansion for Therapeutic Use

“…By regulating the balance of these two signaling pathways, the miR-99a/100∼125b tricistronic miRNAs are reported to promote human HSCs expansion and to favor megakaryocytic diferentiation [143]. Additionally, miR-126 regulates HSC proliferation and diferentiation by targeting PI3K/AKT/mTOR signaling [131]. Regulating these miRNAs may serve as a potential strategy to modulate HSPCs by targeting multiple functional, but opposing, signaling pathways.…”

“…Additional factors or small molecules that enhance UCB HSPC proliferation or function include the Notch Delta-like ligand 1 (DLL1), StemRegenin1 (SR 1), the copper chelator tetraethylenepentamide (TEPA), GSK3 inhibitors of WNT signaling, p18 a speciic inhibitor of cyclin-dependent kinase (CDK), pyrimidoindole derivatives such as UM1 1, speciic miRNAs, and epigenetic modiiers such as histone deacetylase (HDAC) inhibitors and nicotinamide, as well as additional growth factors such as the designer cytokine hyper-IL-6, oncostatin M, IL-11, angiopoietin-like 5, and other angiopoietin-like molecules and IGFBP2 [120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139]. Coculture of UCB cells with mesenchymal stromal cells has also been examined [140].…”