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Bioengineering Seminar Series: Curt I. Civin, M.D.
Friday, April 17, 2009
11:00 a.m.-12:00 p.m.
Room 2110, Chemical and Nuclear Engineering Bldg.
For More Information:
Professor John Fisher

MicroRNA Maestros of Hematopoiesis and Leukemia: Different MicroRNAs Can Positively or Negatively Regulate Differentiation, Proliferation, Apoptosis, and Drug Resistance of Human Leukemia Cells and Normal Hematopoietic Cells

Presented by Curt I. Civin, M.D.
Stem Cell Biology & Regenerative Medicine

Applied Science Engineering
University of Maryland, Baltimore

Based on expression of microRNAs (miRs) and their predicted target messenger RNAs (mRNAs) in human CD34+ hematopoietic stem-progenitor cells (HSPCs), we hypothesized that certain HSPC-expressed microRNAs (HE-miRs) can down-regulate key hematopoietic proteins and thereby regulate hematopoiesis. As a first example, we found that miR-155 was expressed in human CD34+ HSPCs and in mouse Kit+Sca1+Lin- HSPCs (a subset enriched in early HSPCs). MiR-155 was known already to be overexpressed in several types of cancer, including many lymphomas and leukemias. To study the functional role of miR-155 in hematopoiesis and leukemias, we developed molecular tools to efficiently up- and down-regulate miR-155 in hematopoietic cells. To supplement enforced expression experiments using a miR-155/GFP dual promoter lentivector, we lipofected a synthetic 22-mer miR-155 sense oligonucleotide into cells. In functional studies, enforced miR-155 expression increased hematopoietic cell proliferation, in addition to inhibiting hematopoietic differentiation. For loss-of-function experiments, we designed an antisense locked nucleic acid (LNA)-containing antimiR-155 that potently bound to the complementary miR-155. Upon transfection into hematopoietic cells, this LNA antimiR-155 blocked miR-155-mediated inhibition of target mRNAs. Thus, modulation of miR-155 and the pathways it regulates may be useful both in ex vivo expansion of HSPCs and in leukemia treatment.

As a second example, we investigated the action of miR-27a, which appeared to have effects opposite to those of miR-155. In general, miR-27a was expressed at lower (or absent) levels in human leukemias, as compared to normal HSPCs. Lipofection of synthetic miR-27a or lentiviral expression of miR-27a decreased human leukemia cell proliferation. Drug-resistant human leukemia cell lines exhibited increased spontaneous apoptosis and became more susceptible to drug- and growth factor withdrawal-induced apoptosis upon enforced expression of miR-27a. Using luciferase assays, we showed that the anti-apoptotic molecules YWHAQ and PLK2 and the drug-resistance pump ABCC4 were targets of miR-27a. Leukemia cells with enforced miR-27a expression had reduced proliferation and decreased percentages of cells in the G1 cell cycle phase. Certain predicted miR-27a targets may explain this effect on cell cycling. Thus, based on its expression, functional effects, and targets, miR-27a may function as a tumor suppressor miR—lack of miR-27a expression in leukemias may contribute to development and/or progression of these cancers.

This Event is For: Graduate • Faculty • Post-Docs

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