Fasudil, a clinically safe ROCK inhibitor, decreases disease burden in a Cbl/Cbl-b deficiency-driven murine model of myeloproliferative disorders

Basem M. William, Wei An, Dan Feng, Scott Nadeau, Bhopal C. Mohapatra, Matthew A. Storck, Vimla Band, Hamid Band

Research output: Contribution to journalArticle

Abstract

Objectives: Mutations in Cbl or Cbl-b gene occur in 10% of myeloproliferative disorder (MPD) patients and are associated with poor prognosis. Hematopoietic Cbl/Cbl-b double knockout (DKO) leads to a disease in mice phenotypically similar to human MPDs. The aim of this study was to evaluate the anti-MPD activity of a clinically safe drug, Fasudil, identified in an in vitro kinase inhibitor as an inhibitor of proliferation of DKO mouse hematopoietic stem/progenitor cells (HSPCs). Methods: Fasudil exhibited relatively selective anti-proliferative activity against Cbl/Cbl-b DKO vs. control murine bone marrow HSPCs. We established a mouse model with uniform time of MPD onset by transplanting Cbl/Cbl-b DKO HSPCs into busulfan-conditioned NOD/SCID/gamma chain-deficient mice. Four weeks post-transplant, mice were treated with 100 mg/kg fasudil (13 mice) or water (control, 8 mice) daily by oral gavage, followed by blood cell count every 2 weeks. Results: By 2 weeks of treatment, total white cell and monocyte counts were significantly lower in mice treated with fasudil. We observed a trend towards improved survival in fasudil-treated mice that did not reach statistical significance. Notably, prolonged survival beyond 27 weeks was observed in two fasudil-treated mice, nearly twice the 16-week average life-span in the Cbl/Cbl-b DKO MPD model. Conclusions: Our results suggest a therapeutic potential for fasudil, a clinically safe drug with promising results in vascular diseases, in the treatment of MPDs or other mutant Cbl-driven myeloid disorders.

Original languageEnglish (US)
Pages (from-to)218-224
Number of pages7
JournalHematology
Volume21
Issue number4
DOIs
StatePublished - Apr 20 2016

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Myeloproliferative Disorders
Hematopoietic Stem Cells
fasudil
Busulfan
Survival
Blood Cell Count
Vascular Diseases
Knockout Mice
Pharmaceutical Preparations
Monocytes
Phosphotransferases
Therapeutics
Cell Count
Bone Marrow
Transplants
Mutation
Water

Keywords

  • Cbl
  • Fasudil
  • Mouse model
  • Myeloproliferative diseases
  • Myosin light chain
  • Rho kinase

ASJC Scopus subject areas

  • Hematology

Cite this

Fasudil, a clinically safe ROCK inhibitor, decreases disease burden in a Cbl/Cbl-b deficiency-driven murine model of myeloproliferative disorders. / William, Basem M.; An, Wei; Feng, Dan; Nadeau, Scott; Mohapatra, Bhopal C.; Storck, Matthew A.; Band, Vimla; Band, Hamid.

In: Hematology, Vol. 21, No. 4, 20.04.2016, p. 218-224.

Research output: Contribution to journalArticle

William, Basem M. ; An, Wei ; Feng, Dan ; Nadeau, Scott ; Mohapatra, Bhopal C. ; Storck, Matthew A. ; Band, Vimla ; Band, Hamid. / Fasudil, a clinically safe ROCK inhibitor, decreases disease burden in a Cbl/Cbl-b deficiency-driven murine model of myeloproliferative disorders. In: Hematology. 2016 ; Vol. 21, No. 4. pp. 218-224.
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abstract = "Objectives: Mutations in Cbl or Cbl-b gene occur in 10{\%} of myeloproliferative disorder (MPD) patients and are associated with poor prognosis. Hematopoietic Cbl/Cbl-b double knockout (DKO) leads to a disease in mice phenotypically similar to human MPDs. The aim of this study was to evaluate the anti-MPD activity of a clinically safe drug, Fasudil, identified in an in vitro kinase inhibitor as an inhibitor of proliferation of DKO mouse hematopoietic stem/progenitor cells (HSPCs). Methods: Fasudil exhibited relatively selective anti-proliferative activity against Cbl/Cbl-b DKO vs. control murine bone marrow HSPCs. We established a mouse model with uniform time of MPD onset by transplanting Cbl/Cbl-b DKO HSPCs into busulfan-conditioned NOD/SCID/gamma chain-deficient mice. Four weeks post-transplant, mice were treated with 100 mg/kg fasudil (13 mice) or water (control, 8 mice) daily by oral gavage, followed by blood cell count every 2 weeks. Results: By 2 weeks of treatment, total white cell and monocyte counts were significantly lower in mice treated with fasudil. We observed a trend towards improved survival in fasudil-treated mice that did not reach statistical significance. Notably, prolonged survival beyond 27 weeks was observed in two fasudil-treated mice, nearly twice the 16-week average life-span in the Cbl/Cbl-b DKO MPD model. Conclusions: Our results suggest a therapeutic potential for fasudil, a clinically safe drug with promising results in vascular diseases, in the treatment of MPDs or other mutant Cbl-driven myeloid disorders.",
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T1 - Fasudil, a clinically safe ROCK inhibitor, decreases disease burden in a Cbl/Cbl-b deficiency-driven murine model of myeloproliferative disorders

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AU - An, Wei

AU - Feng, Dan

AU - Nadeau, Scott

AU - Mohapatra, Bhopal C.

AU - Storck, Matthew A.

AU - Band, Vimla

AU - Band, Hamid

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AB - Objectives: Mutations in Cbl or Cbl-b gene occur in 10% of myeloproliferative disorder (MPD) patients and are associated with poor prognosis. Hematopoietic Cbl/Cbl-b double knockout (DKO) leads to a disease in mice phenotypically similar to human MPDs. The aim of this study was to evaluate the anti-MPD activity of a clinically safe drug, Fasudil, identified in an in vitro kinase inhibitor as an inhibitor of proliferation of DKO mouse hematopoietic stem/progenitor cells (HSPCs). Methods: Fasudil exhibited relatively selective anti-proliferative activity against Cbl/Cbl-b DKO vs. control murine bone marrow HSPCs. We established a mouse model with uniform time of MPD onset by transplanting Cbl/Cbl-b DKO HSPCs into busulfan-conditioned NOD/SCID/gamma chain-deficient mice. Four weeks post-transplant, mice were treated with 100 mg/kg fasudil (13 mice) or water (control, 8 mice) daily by oral gavage, followed by blood cell count every 2 weeks. Results: By 2 weeks of treatment, total white cell and monocyte counts were significantly lower in mice treated with fasudil. We observed a trend towards improved survival in fasudil-treated mice that did not reach statistical significance. Notably, prolonged survival beyond 27 weeks was observed in two fasudil-treated mice, nearly twice the 16-week average life-span in the Cbl/Cbl-b DKO MPD model. Conclusions: Our results suggest a therapeutic potential for fasudil, a clinically safe drug with promising results in vascular diseases, in the treatment of MPDs or other mutant Cbl-driven myeloid disorders.

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