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Axl activates fibroblast growth factor receptor pathway to potentiate survival signals in B-cell chronic lymphocytic leukemia cells

Leukemia volume 30, pages 1431–1436 (2016)Cite this article

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The fibroblast growth factor (FGF) family and their four receptors, FGFR1/2/3/4, mediate multiple physiologic processes, including cell migration, proliferation, survival and differentiation. FGFRs are expressed on nearly every cell type of hematopoietic origin, and the deregulation of FGFR gene expression and/or gene mutation has been found in hematologic malignancies.1 Given this, we and others have detected that CLL B cells spontaneously produce the basicFGF (bFGF) and CLL plasma contain elevated levels of bFGF.2 However, the precise role of FGF/FGFR signaling pathway in CLL B-cell survival and apoptotic resistance remains undefined.

To validate our findings that CLL B cells primarily express FGFR3, individual FGFRs were immunoprecipitated from equal amount of lysates from CLL B cells or normal B cells followed by western blot analyses to detect FGFR1/R2/R3/R4. As expected, we detected significantly elevated levels of FGFR3 in CLL B cells as compared with normal B cells (Figure 1d). Although we were able to detect FGFR1 (Figure 1b), FGFR2 (Figure 1c) and FGFR4 (Figure 1e) in CLL B cells, the level of expression was comparable with those in normal B cells. Furthermore, significantly higher levels of FGFR3 were also detected on CLL B cells vs normal B cells in flow cytometric analysis (Figures 1f and g). Finally, FGFR3 transcript was detected in CLL B cells by semiquantitative reverse transcriptase-PCR (Supplementary Figure 2) using specific primers (see Supplementary Methods) and confirmed by sequencing the PCR products. Of interest, we also found that exons-8 and -9 of FGFR3 are largely absent in CLL B cells as reverse primers designed for exon-8 or -9 could not amplify the transcript using the forward primer from exon-6, whereas the reverse primer for exon-11 and forward primer at exon-6 amplified FGFR3 transcript (Supplementary Figure 2). Deletions of FGFR3 exons-8–10 have been reported in multiple human malignancies including breast, squamous and osteosarcoma.4 However, an in-depth study is needed to define more clearly the nature of FGFR3 regulation in CLL B cells. In total, our results suggest that CLL B cells overexpress primarily FGFR3.

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Acknowledgements

This work was supported by a research fund from the National Cancer Institute CA170006 to AKG. Collection, processing and deposition of CLL samples into the CLL tissue bank were supported by the Predolin Foundation grant. We also wish to acknowledge Tolero Pharmaceuticals and Novartis for providing the inhibitors to Axl and FGFR, respectively, with relevant information and the excellent secretarial help of Ms Tammy Hughes.

Author contributions

SS performed experiments, analyzed data and created figures; JB and MN performed experiments; SW and DB provided access to the Axl inhibitor TP-0903, and edited manuscript; NEK edited the manuscript; AKG conceived and supervised the project, designed the research, analyzed data and wrote the manuscript; and all authors read and approved the final manuscript.

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Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    S Sinha, J Boysen, M Nelson & N E Kay

  2. Tolero Pharmaceuticals, Inc., Salt Lake City, UT, USA

    S L Warner & D Bearss

  3. Department of Pathology, Stephenson Cancer Center, The University of Oklahoma, Oklahoma City, OK, USA

    A K Ghosh

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  1. S Sinha
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  2. J Boysen
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  7. A K Ghosh
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Correspondence to A K Ghosh.

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Sinha, S., Boysen, J., Nelson, M. et al. Axl activates fibroblast growth factor receptor pathway to potentiate survival signals in B-cell chronic lymphocytic leukemia cells. Leukemia 30, 1431–1436 (2016). https://doi.org/10.1038/leu.2015.323

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