Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS

Li Zhou, Aaron N. Nguyen, Davendra Sohal, Jing Ying Ma, Perry Pahanish, Krishna Gundabolu, Josh Hayman, Adam Chubak, Yongkai Mo, Tushar D. Bhagat, Bhaskar Das, Ann M. Kapoun, Tony A. Navas, Simrit Parmar, Suman Kambhampati, Andrea Pellagatti, Ira Braunchweig, Ying Zhang, Amittha Wickrema, Satyanarayana MedicherlaJacqueline Boultwood, Leonidas C. Platanias, Linda S. Higgins, Alan F. List, Markus Bitzer, Amit Verma

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor-β (TGF-β) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34 + cells, providing direct evidence of overactivation of TGF-β pathway in this disease. Suppression of the TGF-β signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-β-mediated gene activation in BM stromal cells, and reverses TGF-β-mediated cell-cycle arrest in BM CD34 + cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-β1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-β signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.

Original languageEnglish (US)
Pages (from-to)3434-3443
Number of pages10
JournalBlood
Volume112
Issue number8
DOIs
StatePublished - Oct 15 2008

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Growth Factor Receptors
Hematopoiesis
Transforming Growth Factors
Phosphotransferases
Bone
Chemical activation
Bone Marrow
Cell Cycle Checkpoints
Mesenchymal Stromal Cells
Transcriptome
Gene expression
Bone Marrow Cells
Small Interfering RNA
Transcriptional Activation
Anemia
Down-Regulation
Genes
Cells
Molecules
Liver

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Zhou, L., Nguyen, A. N., Sohal, D., Ma, J. Y., Pahanish, P., Gundabolu, K., ... Verma, A. (2008). Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS. Blood, 112(8), 3434-3443. https://doi.org/10.1182/blood-2008-02-139824

Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS. / Zhou, Li; Nguyen, Aaron N.; Sohal, Davendra; Ma, Jing Ying; Pahanish, Perry; Gundabolu, Krishna; Hayman, Josh; Chubak, Adam; Mo, Yongkai; Bhagat, Tushar D.; Das, Bhaskar; Kapoun, Ann M.; Navas, Tony A.; Parmar, Simrit; Kambhampati, Suman; Pellagatti, Andrea; Braunchweig, Ira; Zhang, Ying; Wickrema, Amittha; Medicherla, Satyanarayana; Boultwood, Jacqueline; Platanias, Leonidas C.; Higgins, Linda S.; List, Alan F.; Bitzer, Markus; Verma, Amit.

In: Blood, Vol. 112, No. 8, 15.10.2008, p. 3434-3443.

Research output: Contribution to journalArticle

Zhou, L, Nguyen, AN, Sohal, D, Ma, JY, Pahanish, P, Gundabolu, K, Hayman, J, Chubak, A, Mo, Y, Bhagat, TD, Das, B, Kapoun, AM, Navas, TA, Parmar, S, Kambhampati, S, Pellagatti, A, Braunchweig, I, Zhang, Y, Wickrema, A, Medicherla, S, Boultwood, J, Platanias, LC, Higgins, LS, List, AF, Bitzer, M & Verma, A 2008, 'Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS', Blood, vol. 112, no. 8, pp. 3434-3443. https://doi.org/10.1182/blood-2008-02-139824
Zhou L, Nguyen AN, Sohal D, Ma JY, Pahanish P, Gundabolu K et al. Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS. Blood. 2008 Oct 15;112(8):3434-3443. https://doi.org/10.1182/blood-2008-02-139824
Zhou, Li ; Nguyen, Aaron N. ; Sohal, Davendra ; Ma, Jing Ying ; Pahanish, Perry ; Gundabolu, Krishna ; Hayman, Josh ; Chubak, Adam ; Mo, Yongkai ; Bhagat, Tushar D. ; Das, Bhaskar ; Kapoun, Ann M. ; Navas, Tony A. ; Parmar, Simrit ; Kambhampati, Suman ; Pellagatti, Andrea ; Braunchweig, Ira ; Zhang, Ying ; Wickrema, Amittha ; Medicherla, Satyanarayana ; Boultwood, Jacqueline ; Platanias, Leonidas C. ; Higgins, Linda S. ; List, Alan F. ; Bitzer, Markus ; Verma, Amit. / Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS. In: Blood. 2008 ; Vol. 112, No. 8. pp. 3434-3443.
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abstract = "MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor-β (TGF-β) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34 + cells, providing direct evidence of overactivation of TGF-β pathway in this disease. Suppression of the TGF-β signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-β-mediated gene activation in BM stromal cells, and reverses TGF-β-mediated cell-cycle arrest in BM CD34 + cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-β1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-β signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.",
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AU - Parmar, Simrit

AU - Kambhampati, Suman

AU - Pellagatti, Andrea

AU - Braunchweig, Ira

AU - Zhang, Ying

AU - Wickrema, Amittha

AU - Medicherla, Satyanarayana

AU - Boultwood, Jacqueline

AU - Platanias, Leonidas C.

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