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

• Published in: International journal of hematology 2018-07, Vol.108 (1), p.47-57
• Main Authors: Watanabe, Junichi, Sato, Ken, Osawa, Yukiko, Horiuchi, Toshikatsu, Kato, Shoichiro, Hikota-Saga, Reina, Maekawa, Takaaki, Yamamura, Takeshi, Kobayashi, Ayako, Kobayashi, Shinichi, Kimura, Fumihiko
• Format: Article
• Language: English
• Subjects: Chronic myelomonocytic leukemia; Fever; Glucocorticoids; Granulocyte-macrophage colony-stimulating factor; Hematology; IL-1β; Inflammation; Leukemia; Lipopolysaccharides; Medicine; Medicine & Public Health; Methylprednisolone; Monocytes; Mutation; Myelomonocytic leukemia; Oncology; Original Article; Patients; Phosphorylation; Reduction; Signal transduction; Signaling; Stat5 protein; Therapy; Tumor necrosis factor-α; Tumors
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-018-2436-0

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.