MiR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling

Tushar D. Bhagat, Li Zhou, Lubomir Sokol, Rachel Kessel, Gisela Caceres, Krishna Gundabolu, Roni Tamari, Shanisha Gordon, Ioannis Mantzaris, Tomasz Jodlowski, Yiting Yu, Xiaohong Jing, Rahul Polineni, Kavi Bhatia, Andrea Pellagatti, Jacqueline Boultwood, Suman Kambhampati, Ulrich Steidl, Cy Stein, Wenjun JuGang Liu, Paraic Kenny, Alan List, Markus Bitzer, Amit Verma

Research output: Contribution to journalArticle

70 Citations (Scopus)

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 shownto 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 ofmiR-21 in regulating overactivated TGF-β signaling in MDS.

Original languageEnglish (US)
Pages (from-to)2875-2881
Number of pages7
JournalBlood
Volume121
Issue number15
DOIs
StatePublished - Apr 11 2013

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Myelodysplastic Syndromes
Transforming Growth Factor beta
Hematopoiesis
Bone
Bone Marrow
MicroRNAs
Phosphotransferases
Genes
Binding Sites
Hematocrit
Transgenic Mice
Anemia

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

MiR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling. / Bhagat, Tushar D.; Zhou, Li; Sokol, Lubomir; Kessel, Rachel; Caceres, Gisela; Gundabolu, Krishna; Tamari, Roni; Gordon, Shanisha; Mantzaris, Ioannis; Jodlowski, Tomasz; Yu, Yiting; Jing, Xiaohong; Polineni, Rahul; Bhatia, Kavi; Pellagatti, Andrea; Boultwood, Jacqueline; Kambhampati, Suman; Steidl, Ulrich; Stein, Cy; Ju, Wenjun; Liu, Gang; Kenny, Paraic; List, Alan; Bitzer, Markus; Verma, Amit.

In: Blood, Vol. 121, No. 15, 11.04.2013, p. 2875-2881.

Research output: Contribution to journalArticle

Bhagat, TD, Zhou, L, Sokol, L, Kessel, R, Caceres, G, Gundabolu, K, Tamari, R, Gordon, S, Mantzaris, I, Jodlowski, T, Yu, Y, Jing, X, Polineni, R, Bhatia, K, Pellagatti, A, Boultwood, J, Kambhampati, S, Steidl, U, Stein, C, Ju, W, Liu, G, Kenny, P, List, A, Bitzer, M & Verma, A 2013, 'MiR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling', Blood, vol. 121, no. 15, pp. 2875-2881. https://doi.org/10.1182/blood-2011-12-397067
Bhagat TD, Zhou L, Sokol L, Kessel R, Caceres G, Gundabolu K et al. MiR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling. Blood. 2013 Apr 11;121(15):2875-2881. https://doi.org/10.1182/blood-2011-12-397067
Bhagat, Tushar D. ; Zhou, Li ; Sokol, Lubomir ; Kessel, Rachel ; Caceres, Gisela ; Gundabolu, Krishna ; Tamari, Roni ; Gordon, Shanisha ; Mantzaris, Ioannis ; Jodlowski, Tomasz ; Yu, Yiting ; Jing, Xiaohong ; Polineni, Rahul ; Bhatia, Kavi ; Pellagatti, Andrea ; Boultwood, Jacqueline ; Kambhampati, Suman ; Steidl, Ulrich ; Stein, Cy ; Ju, Wenjun ; Liu, Gang ; Kenny, Paraic ; List, Alan ; Bitzer, Markus ; Verma, Amit. / MiR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling. In: Blood. 2013 ; Vol. 121, No. 15. pp. 2875-2881.
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AU - Bhagat, Tushar D.

AU - Zhou, Li

AU - Sokol, Lubomir

AU - Kessel, Rachel

AU - Caceres, Gisela

AU - Gundabolu, Krishna

AU - Tamari, Roni

AU - Gordon, Shanisha

AU - Mantzaris, Ioannis

AU - Jodlowski, Tomasz

AU - Yu, Yiting

AU - Jing, Xiaohong

AU - Polineni, Rahul

AU - Bhatia, Kavi

AU - Pellagatti, Andrea

AU - Boultwood, Jacqueline

AU - Kambhampati, Suman

AU - Steidl, Ulrich

AU - Stein, Cy

AU - Ju, Wenjun

AU - Liu, Gang

AU - Kenny, Paraic

AU - List, Alan

AU - Bitzer, Markus

AU - Verma, Amit

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N2 - 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 shownto 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 ofmiR-21 in regulating overactivated TGF-β signaling in MDS.

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