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Molecular targets for therapy

Enhanced MAPK signaling is essential for CSF3R-induced leukemia

Leukemia volume 31, pages 1770–1778 (2017)Cite this article

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Abstract

Both membrane-proximal and truncation mutations in CSF3R have recently been reported to drive the onset of chronic neutrophilic leukemia (CNL). Here we show that although truncation mutation alone cannot induce leukemia, both proximal and compound mutations (proximal and truncation mutations on same allele) are leukemogenic with a disease latency of 90 and 23 days, respectively. Comparative whole-genome expression profiling and biochemical experiments revealed that induced expression of Mapk adaptor protein Ksr1 and enhanced Mapk signaling are crucial to leukemogenesis by CSF3R proximal and compound mutants. Moreover, inhibition of Mek1/2 by trametinib alone is sufficient to suppress leukemia induced by both CSF3R proximal and ruxolitinib-resistant compound mutations. Together, these findings elucidate a Mapk-dependent mechanism of CSF3R-induced pathogenesis, and they establish the rationale for clinical evaluation of MEK1/2 inhibition in CNL.

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Acknowledgements

We are thankful to Jose Cancelas for critical reading and suggestions. This study was supported by grants to MA from NCI (1RO1CA155091).

Author contributions

MK, SR, ZK and MA designed and performed experiments and analyzed data. EH, JL, YK and ZS performed in vitro and in vivo experiments. KK analyzed the gene expression data. LG provided intellectual insights and help in designing the experiments. MK and MA wrote the paper. All authors reviewed the manuscript.

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Author notes

  1. S Rohrabaugh, M Kesarwani and Z Kincaid: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    S Rohrabaugh, M Kesarwani, Z Kincaid, E Huber, J Leddonne, Z Siddiqui, Y Khalifa, K Komurov, H L Grimes & M Azam

  2. Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    H L Grimes

  3. Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    M Azam

  4. Department of Pathology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    M Azam

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  1. S Rohrabaugh
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Correspondence to M Azam.

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Rohrabaugh, S., Kesarwani, M., Kincaid, Z. et al. Enhanced MAPK signaling is essential for CSF3R-induced leukemia. Leukemia 31, 1770–1778 (2017). https://doi.org/10.1038/leu.2016.376

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