TY - JOUR
T1 - Fgf2-fgfr1 signaling regulates release of leukemia-protective exosomes from bone marrow stromal cells
AU - Javidi-Sharifi, Nathalie
AU - Martinez, Jacqueline
AU - English, Isabel
AU - Joshi, Sunil K.
AU - Scopim-Ribiero, Renata
AU - Edwards V, David K.
AU - Agarwal, Anupriya
AU - Lopez, Claudia
AU - Jorgens, Danielle
AU - Tyner, Jeffrey W.
AU - Druker, Brian J.
AU - Traer, Elie
N1 - Funding Information:
American Cancer Society MRSG-17-040-1-LIB Elie Traer Howard Hughes Medical Institute Brian J Druker National Institutes of Health 5F30CA186477-03 Javidi-Sharifi Nathalie The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© Javidi-Sharifi et al.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.40033
DO - 10.7554/eLife.40033
M3 - Article
C2 - 30720426
AN - SCOPUS:85061052359
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e40033
ER -