Research Papers:

Targeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models

Qing Wu, Aaron Bhole, Haiyan Qin, Judith Karp, Sami Malek, John K Cowell and Mingqiang Ren _

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Oncotarget. 2016; 7:49733-49742. https://doi.org/10.18632/oncotarget.10438

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Qing Wu1, Aaron Bhole1, Haiyan Qin1, Judith Karp2, Sami Malek3, John K Cowell1, Mingqiang Ren1

1Cancer Center, Georgia Regents University, Augusta, GA, USA

2Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD, USA

3Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA

Correspondence to:

Mingqiang Ren, email: [email protected]

Keywords: AML, FGFR1, therapeutics, NSG-SGM3 mice, xenograft

Received: January 06, 2016     Accepted: June 16, 2016     Published: July 06, 2016


Although over expression of chimeric FGFR1 kinase consistently leads to the development of AML in the rare Stem Cell Leukemia and Lymphoma syndrome, we now show that overexpression of FGFR1 is also seen in up to 20% of non-syndromic, de novo AML. To determine whether targeting FGFR1 in both of these AML subtypes can suppress leukemogenesis, we evaluated the effects of different FGFR1 inhibitors in a side-by-side comparison for their ability to affect in vitro proliferation in FGFR1 overexpressing murine and human cells lines. Three newly developed pan-FGFR inhibitors, AZD4547, BGJ398 and JNJ42756493, show a significantly improved efficacy over the more established FGFR inhibitors, PD173074 and TKI258. To examine whether targeting FGFR1 suppresses leukemogenesis in de novo AML in vivo, we created xenografts in immunocompromized mice from primary, de novo AML that showed > 3-fold increased expression of FGFR1. Using BGJ398, the most potent inhibitor identified in the in vitro studies, AML progression in these mice was significantly suppressed compared with vehicle treated animals and overall survival improved. Importantly, no difference in disease course or survival was seen in AML xenografts that did not show overexpression of FGFR1. These observations support the idea that FGFR1 is a driver oncogene in de novo, FGFR1-overexpressing AML and that molecularly targeted therapies using FGFR1 inhibitors may provide a valuable therapeutic regimen for all FGFR1-overexpressing AML.

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