[show abstract][hide abstract] ABSTRACT: The microRNA miR-150, a critical regulator of hematopoiesis, is downregulated in MLL-associated leukemias. In this study, we demonstrate that miR-150 acts as a potent leukemic tumor suppressor by blocking the oncogenic properties of leukemic cells. By using murine MLL-AF9 transformed cells, we demonstrate that miR-150 ectopic expression inhibits blast colony formation and cell growth and increases apoptosis in vitro. More importantly, ectopic expression of miR-150 in transformed MLL-AF9 cells completely blocked the development of myeloid leukemia in transplanted mice. Gene expression profiles demonstrated that miR-150 altered the expression levels of more than 30 "stem cell signature" genes and many others that are involved in cancer pathways. Furthermore, we identified Cbl and Egr2, additional to the known target Myb, as bona fide miR-150 targets, and knockdown of these genes by shRNAs recapitulated the pro-apoptotic effects observed in leukemic cells with miR-150 ectopic expression. In conclusion, we demonstrate that miR-150 is a potent leukemic tumor suppressor that regulates multiple oncogenes, providing new key players for the development of therapeutic strategies to treat MLL-AF9 related leukemia.
Molecular Cancer Research 04/2013; · 4.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: Macrophage activation plays a crucial role in regulating adipose tissue inflammation and is a major contributor to the pathogenesis of obesity-associated cardiovascular diseases. On various types of stimuli, macrophages respond with either classic (M1) or alternative (M2) activation. M1- and M2-mediated signaling pathways and corresponding cytokine production profiles are not completely understood. The discovery of microRNAs provides a new opportunity to understand this complicated but crucial network for macrophage activation and adipose tissue function.
We have examined the activity of microRNA-223 (miR-223) and its role in controlling macrophage functions in adipose tissue inflammation and systemic insulin resistance. miR-223(-/-) mice on a high-fat diet exhibited an increased severity of systemic insulin resistance compared with wild-type mice that was accompanied by a marked increase in adipose tissue inflammation. The specific regulatory effects of miR-223 in myeloid cell-mediated regulation of adipose tissue inflammation and insulin resistance were then confirmed by transplantation analysis. Moreover, using bone marrow-derived macrophages, we demonstrated that miR-223 is a novel regulator of macrophage polarization, which suppresses classic proinflammatory pathways and enhances the alternative antiinflammatory responses. In addition, we identified Pknox1 as a genuine miR-223 target gene and an essential regulator for macrophage polarization.
For the first time, this study demonstrates that miR-223 acts to inhibit Pknox1, suppressing proinflammatory activation of macrophages; thus, it is a crucial regulator of macrophage polarization and protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance.
Editorial: A MicroRNA Circuitry Links Macrophage Polarization to Metabolic Homeostasis Meng ZX, Wang GX, Lin JD. Circulation. 2012 Jun 12;125(23):2815-7. Epub 2012 May 11. PMID: 22580332
[show abstract][hide abstract] ABSTRACT: The mixed lineage leukemia (MLL) gene codes for an evolutionarily conserved histone methyltransferase that is crucial for early hematopoiesis. As a result of a chromosomal translocation involving locus 11q23 results in formation of chimeras composed of the 5’ part of the MLL gene fused with more than 60 partner genes lead to disruption of normal function of MLL as a histone methytransferase and acquisition of transcriptional properties conferred by the partner genes. MLL fusion genes (MLL-FG) are often the causal mutations for aggressive acute myeloid and lymphoid leukemias (AML and ALL) that correlated with poor prognosis. In order to treat or even eliminate MLL-associated leukemias, extensive studies on the regulatory mechanism underlying MLL associated transformation and progression have been carried out. Leukemic stem cells (LSC) can derive from either hematopoietic stem or progenitor cells with the recruitment of MLL-fusion genes (MLL-FG) and wild type MLL protein.
We report that miR-150, a key hematopoietic regulatory microRNA (miRNA) and one of the most downregulated miRNAs in MLL-associated leukemias, acts as a tumor suppressor to block the leukemogenic potency of leukemic stem cells. When expression of miR-150 was restored, a significantly suppressed leukemic stem cell potency of MLL-AF9 cells was observed both in vivo and in vitro. Gene profiling analysis demonstrated that elevated miR-150 altered various aspects of gene expression patterns in MLL-AF9 cells, including stem cell signatures, cancer pathways, and cell survival. By screening more than 30 predicted target genes, we identified multiple leukemia-associated oncogenes as bona fide miR-150 targets, and knockdown of these genes by shRNAs recapitulated the tumor suppressive effects observed after ectopically expression of miR-150 in MLL-AF9 cells.