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CBL mutation and MEFV single-nucleotide variant are important genetic predictors of tumor reduction in glucocorticoid-treated patients with chronic myelomonocytic leukemia

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Abstract

Glucocorticoid (GC) therapy occasionally relieves tumor-related fever and promotes tumor reduction in patients with chronic myelomonocytic leukemia (CMML). A mutation analysis of 24 patients with CMML revealed the relationship of GC effectiveness, defined as a monocyte reduction of > 50% within 3 days of methylprednisolone administration, with the MEFV single-nucleotide variant (SNV) and CBL mutation. Lipopolysaccharide-stimulated monocytes harboring MEFV E148Q produced greater amounts of IL-1β and TNF-α than did wild-type monocytes; this was effectively suppressed by GC. Primary CMML cells harboring the MEFV SNV and CBL mutation, and the myelomonocytic leukemia cell line GDM-1, harboring the CBL mutation, were both more significantly suppressed than non-mutated cells following GC treatment in the presence of GM-CSF. A loss-of-function CBL mutation prolonged STAT5 phosphorylation after GM-CSF stimulation, which was rapidly terminated in both patient samples and GDM-1 cells. In conclusion, GC therapy effectively treats CMML cells harboring the MEFV SNV and CBL mutation by reducing inflammatory cytokine production and terminating prolonged STAT5 phosphorylation in the GM-CSF signaling pathway.

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Acknowledgements

This work was partially supported by a research grant from Merck, Sharp, and Dohme (MSD).

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Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Junichi Watanabe, Ken Sato, Yukiko Osawa, Toshikatsu Horiuchi, Shoichiro Kato, Reina Hikota-Saga, Takaaki Maekawa, Takeshi Yamamura, Ayako Kobayashi, Shinichi Kobayashi & Fumihiko Kimura

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  1. Junichi Watanabe
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Contributions

JW and FK designed this study. JW performed all experiments and wrote the paper. YO provided support for the sequencing analysis and ELISA. JW performed statistical analyses. FK, SK, and KS commented on the draft. JW, TH, SK, RH-S. TM, TY, and AK collected data. All authors reviewed the final version of the manuscript.

Corresponding author

Correspondence to Fumihiko Kimura.

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Conflict of interest

FK has received a research grant from Merck, Sharp, and Dohme (MSD) for this study. The remaining authors declare no competing financial interests.

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Watanabe, J., Sato, K., Osawa, Y. et al. CBL mutation and MEFV single-nucleotide variant are important genetic predictors of tumor reduction in glucocorticoid-treated patients with chronic myelomonocytic leukemia. Int J Hematol 108, 47–57 (2018). https://doi.org/10.1007/s12185-018-2436-0

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  • DOI: https://doi.org/10.1007/s12185-018-2436-0

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