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International Journal of Hematology

, Volume 108, Issue 1, pp 47–57 | Cite as

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

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

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.

Keywords

Chronic myelomonocytic leukemia CBL MEFV Glucocorticoid 

Notes

Acknowledgements

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

Author 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.

Compliance with ethical standards

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.

Supplementary material

12185_2018_2436_MOESM1_ESM.docx (1.4 mb)
Supplementary material 1 (DOCX 1405 kb)

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Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Junichi Watanabe
    • 1
  • Ken Sato
    • 1
  • Yukiko Osawa
    • 1
  • Toshikatsu Horiuchi
    • 1
  • Shoichiro Kato
    • 1
  • Reina Hikota-Saga
    • 1
  • Takaaki Maekawa
    • 1
  • Takeshi Yamamura
    • 1
  • Ayako Kobayashi
    • 1
  • Shinichi Kobayashi
    • 1
  • Fumihiko Kimura
    • 1
  1. 1.Division of Hematology, Department of Internal MedicineNational Defense Medical CollegeTokorozawaJapan

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