KIT-D816V–independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk activation and disruption by dasatinib and bosutinib

• Published in: Blood Vol. 118; no. 7; pp. 1885 - 1898
• Main Authors: Gleixner, Karoline V., Mayerhofer, Matthias, Cerny-Reiterer, Sabine, Hörmann, Gregor, Rix, Uwe, Bennett, Keiryn L., Hadzijusufovic, Emir, Meyer, Renata A., Pickl, Winfried F., Gotlib, Jason, Horny, Hans-Peter, Reiter, Andreas, Mitterbauer-Hohendanner, Gerlinde, Superti-Furga, Giulio, Valent, Peter
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 18.08.2011; Americain Society of Hematology
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Aniline Compounds - pharmacology; Biological and medical sciences; Cell Line, Tumor; Dasatinib; Drug Synergism; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Mast Cells - metabolism; Mast Cells - pathology; Mastocytosis, Systemic - drug therapy; Mastocytosis, Systemic - genetics; Mastocytosis, Systemic - metabolism; Medical sciences; Mutation; Nitriles - pharmacology; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Pyrimidines - pharmacology; Quinolines - pharmacology; Signal Transduction - drug effects; src-Family Kinases - genetics; src-Family Kinases - metabolism; Staurosporine - analogs & derivatives; Staurosporine - pharmacology; Thiazoles - pharmacology; Tumor Cells, Cultured; Antineoplastic agent; Dasatinib; Hematology; Enzyme; Tyrosine kinase inhibitor; Transferases; Lyn protein tyrosine kinase; Malignant hemopathy; Malignant tumor; Bosutinib; Systemic mastocytosis; Signal transduction; Bruton tyrosine kinase; Multikinase inhibitor; Protein-tyrosine kinase; Protooncogene; Cancer
• DOI: 10.1182/blood-2010-06-289959
• ISSN: 0006-4971; 1528-0020

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.