FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells

Nathalie Javidi-Sharifi, Jacqueline Martinez, Isabel English, Sunil K. Joshi, Renata Scopim-Ribiero, David K. Edwards, Anupriya Agarwal, Claudia Lopez, Danielle Jorgens, Jeffrey Tyner, Brian Druker, Elie Traer

Research output: Contribution to journalArticle

Abstract

Protective signaling from the leukemia microenvironment leads to leukemia cell persistence, development of resistance, and disease relapse. Here, we demonstrate that fibroblast growth factor 2 (FGF2) from bone marrow stromal cells is secreted in exosomes, which are subsequently endocytosed by leukemia cells, and protect leukemia cells from tyrosine kinase inhibitors (TKIs). Expression of FGF2 and its receptor, FGFR1, are both increased in a subset of stromal cell lines and primary AML stroma; and increased FGF2/FGFR1 signaling is associated with increased exosome secretion. FGFR inhibition (or gene silencing) interrupts stromal autocrine growth and significantly decreases secretion of FGF2-containing exosomes, resulting in less stromal protection of leukemia cells. Likewise, Fgf2 -/- mice transplanted with retroviral BCR-ABL leukemia survive significantly longer than their +/+ counterparts when treated with TKI. Thus, inhibition of FGFR can modulate stromal function, reduce exosome secretion, and may be a therapeutic option to overcome resistance to TKIs. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - Feb 5 2019

Fingerprint

Exosomes
Fibroblast Growth Factor 2
Mesenchymal Stromal Cells
Protein-Tyrosine Kinases
Bone
Leukemia
Receptor, Fibroblast Growth Factor, Type 2
Genes
Cells
Peer Review
Disease Resistance
Cytoprotection
Gene Silencing
Stromal Cells
Endocytosis
Recurrence
Cell Line
Growth

Keywords

  • bone marrow stroma
  • cancer biology
  • drug resistance
  • exosomes
  • FGF2
  • FGFR1
  • human
  • human biology
  • medicine
  • microenvironment
  • mouse

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Javidi-Sharifi, N., Martinez, J., English, I., Joshi, S. K., Scopim-Ribiero, R., Edwards, D. K., ... Traer, E. (2019). FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells. eLife, 8. https://doi.org/10.7554/eLife.40033

FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells. / Javidi-Sharifi, Nathalie; Martinez, Jacqueline; English, Isabel; Joshi, Sunil K.; Scopim-Ribiero, Renata; Edwards, David K.; Agarwal, Anupriya; Lopez, Claudia; Jorgens, Danielle; Tyner, Jeffrey; Druker, Brian; Traer, Elie.

In: eLife, Vol. 8, 05.02.2019.

Research output: Contribution to journalArticle

Javidi-Sharifi N, Martinez J, English I, Joshi SK, Scopim-Ribiero R, Edwards DK et al. FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells. eLife. 2019 Feb 5;8. https://doi.org/10.7554/eLife.40033
Javidi-Sharifi, Nathalie ; Martinez, Jacqueline ; English, Isabel ; Joshi, Sunil K. ; Scopim-Ribiero, Renata ; Edwards, David K. ; Agarwal, Anupriya ; Lopez, Claudia ; Jorgens, Danielle ; Tyner, Jeffrey ; Druker, Brian ; Traer, Elie. / FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells. In: eLife. 2019 ; Vol. 8.
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