title: KIT-D816V-independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk activation and disruption by dasatinib and bosutinib.
abstract: Systemic mastocytosis (SM) either presents as a malignant neoplasm with short survival or as an indolent disease with normal life expectancy. In both instances, neoplastic mast cells (MCs) harbor D816V-mutated KIT, suggesting that additional oncogenic mechanisms are involved in malignant transformation. We here describe that Lyn and Btk are phosphorylated in a KIT-independent manner in neoplastic MCs in advanced SM and in the MC leukemia cell line HMC-1. Lyn and Btk activation was not only detected in KIT D816V-positive HMC-1.2 cells, but also in the KIT D816V-negative HMC-1.1 subclone. Moreover, KIT D816V did not induce Lyn/Btk activation in Ba/F3 cells, and deactivation of KIT D816V by midostaurin did not alter Lyn/Btk activation. siRNAs against Btk and Lyn were found to block survival in neoplastic MCs and to cooperate with midostaurin in producing growth inhibition. Growth inhibitory effects were also obtained with 2 targeted drugs, dasatinib which blocks KIT, Lyn, and Btk activation in MCs, and bosutinib, a drug that deactivates Lyn and Btk without blocking KIT activity. Together, KIT-independent signaling via Lyn/Btk contributes to growth of neoplastic MCs in advanced SM. Dasatinib and bosutinib disrupt Lyn/Btk-driven oncogenic signaling in neoplastic MC, which may have clinical implications and explain synergistic drug interactions.
authors.affiliation: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors.forename: Karoline V
authors.initials: KV
authors.lastname: Gleixner
authors.forename: Matthias
authors.initials: M
authors.lastname: Mayerhofer
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.forename: Gregor
authors.initials: G
authors.lastname: Hörmann
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Emir
authors.initials: E
authors.lastname: Hadzijusufovic
authors.forename: Renata A
authors.initials: RA
authors.lastname: Meyer
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Horny
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Mitterbauer-Hohendanner
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000814:Aniline Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D013844:Thiazoles; C471992:bosutinib; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D019311:Staurosporine; C059539:midostaurin; D000069439:Dasatinib