Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease

Sonia D'Souza, Davide Del Prete, Shunqian Jin, Quanhong Sun, Alissa J. Huston, Flavia Esteve Kostov, Benedicte Sammut, Chang Sook Hong, Judith L. Anderson, Kenneth D. Patrene, Shibing Yu, Chinavenmeni S. Velu, Guozhi Xiao, H. Leighton Grimes, G. David Roodman, Deborah L. Galson

Research output: Contribution to journalArticle

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Abstract

Protracted inhibition of osteoblast (OB) differentiation characterizes multiple myeloma (MM) bone disease and persists even when patients are in long-term remission. However, the underlying pathophysiology for this prolonged OB suppression is unknown. Therefore, we developed a mouse MM model in which the bone marrow stromal cells (BMSCs) remained unresponsive to OB differentiation signals after removal of MM cells. We found that BMSCs from both MM-bearing mice and MM patients had increased levels of the transcriptional repressor Gfi1 compared with controls and that Gfi1 was a novel transcriptional repressor of the critical OB transcription factor Runx2. Trichostatin-A blocked the effects of Gfi1, suggesting that it induces epigenetic changes in the Runx2 promoter. MM-BMSC cell-cell contact was not required for MM cells to increase Gfi1 and repress Runx2 levels in MC-4 before OBs or naive primary BMSCs, and Gfi1 induction was blocked by anti-TNF-α and anti-IL-7 antibodies. Importantly, BMSCs isolated from Gfi1 -/- mice were significantly resistant to MMinduced OB suppression. Strikingly, siRNA knockdown of Gfi1 in BMSCs from MMpatients significantly restored expression of Runx2 and OB differentiation markers. Thus, Gfi1 may have an important role in prolonged MM-induced OB suppression and provide a new therapeutic target for MM bone disease.

Original languageEnglish (US)
Pages (from-to)6871-6880
Number of pages10
JournalBlood
Volume118
Issue number26
DOIs
StatePublished - Dec 22 2011
Externally publishedYes

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Bone Diseases
Osteoblasts
Multiple Myeloma
Mesenchymal Stromal Cells
Bone
trichostatin A
Bearings (structural)
Interleukin-7
Differentiation Antigens
Small Interfering RNA
Epigenomics
Transcription Factors
Antibodies

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

D'Souza, S., Del Prete, D., Jin, S., Sun, Q., Huston, A. J., Kostov, F. E., ... Galson, D. L. (2011). Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease. Blood, 118(26), 6871-6880. https://doi.org/10.1182/blood-2011-04-346775

Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease. / D'Souza, Sonia; Del Prete, Davide; Jin, Shunqian; Sun, Quanhong; Huston, Alissa J.; Kostov, Flavia Esteve; Sammut, Benedicte; Hong, Chang Sook; Anderson, Judith L.; Patrene, Kenneth D.; Yu, Shibing; Velu, Chinavenmeni S.; Xiao, Guozhi; Grimes, H. Leighton; Roodman, G. David; Galson, Deborah L.

In: Blood, Vol. 118, No. 26, 22.12.2011, p. 6871-6880.

Research output: Contribution to journalArticle

D'Souza, S, Del Prete, D, Jin, S, Sun, Q, Huston, AJ, Kostov, FE, Sammut, B, Hong, CS, Anderson, JL, Patrene, KD, Yu, S, Velu, CS, Xiao, G, Grimes, HL, Roodman, GD & Galson, DL 2011, 'Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease', Blood, vol. 118, no. 26, pp. 6871-6880. https://doi.org/10.1182/blood-2011-04-346775
D'Souza, Sonia ; Del Prete, Davide ; Jin, Shunqian ; Sun, Quanhong ; Huston, Alissa J. ; Kostov, Flavia Esteve ; Sammut, Benedicte ; Hong, Chang Sook ; Anderson, Judith L. ; Patrene, Kenneth D. ; Yu, Shibing ; Velu, Chinavenmeni S. ; Xiao, Guozhi ; Grimes, H. Leighton ; Roodman, G. David ; Galson, Deborah L. / Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease. In: Blood. 2011 ; Vol. 118, No. 26. pp. 6871-6880.
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abstract = "Protracted inhibition of osteoblast (OB) differentiation characterizes multiple myeloma (MM) bone disease and persists even when patients are in long-term remission. However, the underlying pathophysiology for this prolonged OB suppression is unknown. Therefore, we developed a mouse MM model in which the bone marrow stromal cells (BMSCs) remained unresponsive to OB differentiation signals after removal of MM cells. We found that BMSCs from both MM-bearing mice and MM patients had increased levels of the transcriptional repressor Gfi1 compared with controls and that Gfi1 was a novel transcriptional repressor of the critical OB transcription factor Runx2. Trichostatin-A blocked the effects of Gfi1, suggesting that it induces epigenetic changes in the Runx2 promoter. MM-BMSC cell-cell contact was not required for MM cells to increase Gfi1 and repress Runx2 levels in MC-4 before OBs or naive primary BMSCs, and Gfi1 induction was blocked by anti-TNF-α and anti-IL-7 antibodies. Importantly, BMSCs isolated from Gfi1 -/- mice were significantly resistant to MMinduced OB suppression. Strikingly, siRNA knockdown of Gfi1 in BMSCs from MMpatients significantly restored expression of Runx2 and OB differentiation markers. Thus, Gfi1 may have an important role in prolonged MM-induced OB suppression and provide a new therapeutic target for MM bone disease.",
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AU - Sun, Quanhong

AU - Huston, Alissa J.

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AU - Sammut, Benedicte

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AU - Anderson, Judith L.

AU - Patrene, Kenneth D.

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AU - Velu, Chinavenmeni S.

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