title: miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling.
abstract: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis that leads to peripheral cytopenias. We observed that SMAD7, a negative regulator of transforming growth factor-beta (TGF-β) receptor-I kinase, is markedly reduced in MDS and leads to ineffective hematopoiesis by overactivation of TGF-β signaling. To determine the cause of SMAD7 reduction in MDS, we analyzed the 3'UTR of the gene and determined that it contains a highly conserved putative binding site for microRNA-21. We observed significantly elevated levels of miR-21 in MDS marrow samples when compared with age-matched controls. miR-21 was shown to directly bind to the 3'UTR of SMAD7 and reduce its expression in hematopoietic cells. Next, we tested the role of miR-21 in regulating TGF-β signaling in a TGF-β-overexpressing transgenic mouse model that develops progressive anemia and dysplasia and thus serves as a model of human bone marrow failure. Treatment with a chemically modified miR-21 inhibitor led to significant increases in hematocrit and led to an increase in SMAD7 expression in vivo. Inhibition of miR-21 also led to an increase in erythroid colony formation from primary MDS bone marrow progenitors, demonstrating its ability in stimulating hematopoiesis in vitro. Taken together, these studies demonstrate the role of miR-21 in regulating overactivated TGF-β signaling in MDS.
authors: Albert Einstein College of Medicine, Bronx, NY;
authors: Tushar D
authors: TD
authors: Bhagat
authors: Li
authors: L
authors: Zhou
authors: Lubomir
authors: L
authors: Sokol
authors: Rachel
authors: R
authors: Kessel
authors: Gisela
authors: G
authors: Caceres
authors: Krishna
authors: K
authors: Gundabolu
authors: Roni
authors: R
authors: Tamari
authors: Shanisha
authors: S
authors: Gordon
authors: Ioannis
authors: I
authors: Mantzaris
authors: Tomasz
authors: T
authors: Jodlowski
authors: Yiting
authors: Y
authors: Yu
authors: Xiaohong
authors: X
authors: Jing
authors: Rahul
authors: R
authors: Polineni
authors: Kavi
authors: K
authors: Bhatia
authors: Andrea
authors: A
authors: Pellagatti
authors: Jacqueline
authors: J
authors: Boultwood
authors: Suman
authors: S
authors: Kambhampati
authors: Ulrich
authors: U
authors: Steidl
authors: Cy
authors: C
authors: Stein
authors: Wenjun
authors: W
authors: Ju
authors: Gang
authors: G
authors: Liu
authors: Paraic
authors: P
authors: Kenny
authors: Alan
authors: A
authors: List
authors: Markus
authors: M
authors: Bitzer
authors: Amit
authors: A
authors: Verma
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D020014:K562 Cells; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D051906:Smad7 Protein / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; D049452:Green Fluorescent Proteins
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