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

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 leukem...
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Autor*in:	Nathalie Javidi-Sharifi [verfasserIn] Jacqueline Martinez [verfasserIn] Isabel English [verfasserIn] Sunil K Joshi [verfasserIn] Renata Scopim-Ribeiro [verfasserIn] Shelton K Viola [verfasserIn] David K Edwards V [verfasserIn] Anupriya Agarwal [verfasserIn] Claudia Lopez [verfasserIn] Danielle Jorgens [verfasserIn] Jeffrey W Tyner [verfasserIn] Brian J Druker [verfasserIn] Elie Traer [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	FGF2 FGFR1 exosomes bone marrow stroma microenvironment drug resistance

Übergeordnetes Werk:	In: eLife - eLife Sciences Publications Ltd, 2013, 8(2019)
Übergeordnetes Werk:	volume:8 ; year:2019

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.7554/eLife.40033

Katalog-ID:	DOAJ031854834

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520			\|a 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).
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allfields	10.7554/eLife.40033 doi (DE-627)DOAJ031854834 (DE-599)DOAJ1c66ad09cee24491a3ce0b7b0754affd DE-627 ger DE-627 rakwb eng QH301-705.5 Nathalie Javidi-Sharifi verfasserin aut FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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). FGF2 FGFR1 exosomes bone marrow stroma microenvironment drug resistance Medicine R Science Q Biology (General) Jacqueline Martinez verfasserin aut Isabel English verfasserin aut Sunil K Joshi verfasserin aut Renata Scopim-Ribeiro verfasserin aut Shelton K Viola verfasserin aut David K Edwards V verfasserin aut Anupriya Agarwal verfasserin aut Claudia Lopez verfasserin aut Danielle Jorgens verfasserin aut Jeffrey W Tyner verfasserin aut Brian J Druker verfasserin aut Elie Traer verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 8(2019) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:8 year:2019 https://doi.org/10.7554/eLife.40033 kostenfrei https://doaj.org/article/1c66ad09cee24491a3ce0b7b0754affd kostenfrei https://elifesciences.org/articles/40033 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2019
spelling	10.7554/eLife.40033 doi (DE-627)DOAJ031854834 (DE-599)DOAJ1c66ad09cee24491a3ce0b7b0754affd DE-627 ger DE-627 rakwb eng QH301-705.5 Nathalie Javidi-Sharifi verfasserin aut FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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). FGF2 FGFR1 exosomes bone marrow stroma microenvironment drug resistance Medicine R Science Q Biology (General) Jacqueline Martinez verfasserin aut Isabel English verfasserin aut Sunil K Joshi verfasserin aut Renata Scopim-Ribeiro verfasserin aut Shelton K Viola verfasserin aut David K Edwards V verfasserin aut Anupriya Agarwal verfasserin aut Claudia Lopez verfasserin aut Danielle Jorgens verfasserin aut Jeffrey W Tyner verfasserin aut Brian J Druker verfasserin aut Elie Traer verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 8(2019) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:8 year:2019 https://doi.org/10.7554/eLife.40033 kostenfrei https://doaj.org/article/1c66ad09cee24491a3ce0b7b0754affd kostenfrei https://elifesciences.org/articles/40033 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2019
allfields_unstemmed	10.7554/eLife.40033 doi (DE-627)DOAJ031854834 (DE-599)DOAJ1c66ad09cee24491a3ce0b7b0754affd DE-627 ger DE-627 rakwb eng QH301-705.5 Nathalie Javidi-Sharifi verfasserin aut FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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). FGF2 FGFR1 exosomes bone marrow stroma microenvironment drug resistance Medicine R Science Q Biology (General) Jacqueline Martinez verfasserin aut Isabel English verfasserin aut Sunil K Joshi verfasserin aut Renata Scopim-Ribeiro verfasserin aut Shelton K Viola verfasserin aut David K Edwards V verfasserin aut Anupriya Agarwal verfasserin aut Claudia Lopez verfasserin aut Danielle Jorgens verfasserin aut Jeffrey W Tyner verfasserin aut Brian J Druker verfasserin aut Elie Traer verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 8(2019) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:8 year:2019 https://doi.org/10.7554/eLife.40033 kostenfrei https://doaj.org/article/1c66ad09cee24491a3ce0b7b0754affd kostenfrei https://elifesciences.org/articles/40033 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2019
allfieldsGer	10.7554/eLife.40033 doi (DE-627)DOAJ031854834 (DE-599)DOAJ1c66ad09cee24491a3ce0b7b0754affd DE-627 ger DE-627 rakwb eng QH301-705.5 Nathalie Javidi-Sharifi verfasserin aut FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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). FGF2 FGFR1 exosomes bone marrow stroma microenvironment drug resistance Medicine R Science Q Biology (General) Jacqueline Martinez verfasserin aut Isabel English verfasserin aut Sunil K Joshi verfasserin aut Renata Scopim-Ribeiro verfasserin aut Shelton K Viola verfasserin aut David K Edwards V verfasserin aut Anupriya Agarwal verfasserin aut Claudia Lopez verfasserin aut Danielle Jorgens verfasserin aut Jeffrey W Tyner verfasserin aut Brian J Druker verfasserin aut Elie Traer verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 8(2019) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:8 year:2019 https://doi.org/10.7554/eLife.40033 kostenfrei https://doaj.org/article/1c66ad09cee24491a3ce0b7b0754affd kostenfrei https://elifesciences.org/articles/40033 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2019
allfieldsSound	10.7554/eLife.40033 doi (DE-627)DOAJ031854834 (DE-599)DOAJ1c66ad09cee24491a3ce0b7b0754affd DE-627 ger DE-627 rakwb eng QH301-705.5 Nathalie Javidi-Sharifi verfasserin aut FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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). FGF2 FGFR1 exosomes bone marrow stroma microenvironment drug resistance Medicine R Science Q Biology (General) Jacqueline Martinez verfasserin aut Isabel English verfasserin aut Sunil K Joshi verfasserin aut Renata Scopim-Ribeiro verfasserin aut Shelton K Viola verfasserin aut David K Edwards V verfasserin aut Anupriya Agarwal verfasserin aut Claudia Lopez verfasserin aut Danielle Jorgens verfasserin aut Jeffrey W Tyner verfasserin aut Brian J Druker verfasserin aut Elie Traer verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 8(2019) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:8 year:2019 https://doi.org/10.7554/eLife.40033 kostenfrei https://doaj.org/article/1c66ad09cee24491a3ce0b7b0754affd kostenfrei https://elifesciences.org/articles/40033 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2019
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callnumber-first	Q - Science
author	Nathalie Javidi-Sharifi
spellingShingle	Nathalie Javidi-Sharifi misc QH301-705.5 misc FGF2 misc FGFR1 misc exosomes misc bone marrow stroma misc microenvironment misc drug resistance misc Medicine misc R misc Science misc Q misc Biology (General) FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells
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topic_title	QH301-705.5 FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells FGF2 FGFR1 exosomes bone marrow stroma microenvironment drug resistance
topic	misc QH301-705.5 misc FGF2 misc FGFR1 misc exosomes misc bone marrow stroma misc microenvironment misc drug resistance misc Medicine misc R misc Science misc Q misc Biology (General)
topic_unstemmed	misc QH301-705.5 misc FGF2 misc FGFR1 misc exosomes misc bone marrow stroma misc microenvironment misc drug resistance misc Medicine misc R misc Science misc Q misc Biology (General)
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title	FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells
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title_full	FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells
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author_browse	Nathalie Javidi-Sharifi Jacqueline Martinez Isabel English Sunil K Joshi Renata Scopim-Ribeiro Shelton K Viola David K Edwards V Anupriya Agarwal Claudia Lopez Danielle Jorgens Jeffrey W Tyner Brian J Druker Elie Traer
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title_sort	fgf2-fgfr1 signaling regulates release of leukemia-protective exosomes from bone marrow stromal cells
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title_auth	FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells
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).
abstractGer	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).
abstract_unstemmed	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).
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title_short	FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells
url	https://doi.org/10.7554/eLife.40033 https://doaj.org/article/1c66ad09cee24491a3ce0b7b0754affd https://elifesciences.org/articles/40033 https://doaj.org/toc/2050-084X
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author2	Jacqueline Martinez Isabel English Sunil K Joshi Renata Scopim-Ribeiro Shelton K Viola David K Edwards V Anupriya Agarwal Claudia Lopez Danielle Jorgens Jeffrey W Tyner Brian J Druker Elie Traer
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up_date	2024-07-03T22:47:47.279Z
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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. 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FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells

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