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Acute myeloid leukemia

FGFR1 fusion kinase regulation of MYC expression drives development of stem cell leukemia/lymphoma syndrome

Leukemia volume 32, pages 2363–2373 (2018)Cite this article

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Abstract

Oncogenic transformation of hematopoietic stem cells by chimeric fusion kinases causing constitutive activation of FGFR1 leads to a stem cell leukemia/lymphoma (SCLL) syndrome, accompanied by widespread dysregulation of gene activity. We now show that FGFR1 activation is associated with upregulation of MYC and pharmacological suppression of FGFR1 activation leads to downregulation of MYC and suppression of MYC target genes. Luciferase reporter assays demonstrate that FGFR1 can directly regulate MYC expression and this effect is enhanced in the presence of chimeric FGFR1 kinases. In SCLL cells, a truncated form of FGFR1 is generated by granzyme B cleavage of the chimeric kinases, producing a nucleus-restricted derivative that can bind MYC regulatory regions. Mutation of the granzyme B cleavage site prevents relocation to the nucleus but does not suppress MYC activation, suggesting additional mechanisms of MYC activation in the presence of cytoplasm-restricted chimeric kinases. We show that one of these mechanisms involves activating cytoplasmic STAT5, which upregulates MYC independent of the truncated FGFR1 kinase. Targeting MYC function using shRNA knockdown and 10054-F8 in SCLL cells leads to inhibition of cell proliferation and synergizes with the BGJ398 FGFR1 inhibitor, suggesting a combination therapy that could be used in the treatment of SCLL.

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Acknowledgements

This work was supported by grant CA076167 from the National Institutes of Health.

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Authors and Affiliations

  1. Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA

    Tianxiang Hu, Qing Wu, Yating Chong, Haiyan Qin & John K. Cowell

  2. Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA

    Candace J. Poole & Jan van Riggelen

  3. Consortium for Health and Military Performance (CHAMP), Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA

    Mingqiang Ren

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  1. Tianxiang Hu
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Correspondence to Mingqiang Ren or John K. Cowell.

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Hu, T., Wu, Q., Chong, Y. et al. FGFR1 fusion kinase regulation of MYC expression drives development of stem cell leukemia/lymphoma syndrome. Leukemia 32, 2363–2373 (2018). https://doi.org/10.1038/s41375-018-0124-y

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