title: Oncogenic KIT-induced aggressive systemic mastocytosis requires SHP2/PTPN11 phosphatase for disease progression in mice.
abstract: Acquired mutations in KIT are driver mutations in systemic mastocytosis (SM). Here, we tested the role of SHP2/PTPN11 phosphatase in oncogenic KIT signaling using an aggressive SM mouse model. Stable knock-down (KD) of SHP2 led to impaired growth, colony formation, and increased rates of apoptosis in P815 cells. This correlated with defects in signaling to ERK/Bim, Btk, Lyn, and Stat5 pathways in P815-KD cells compared to non-targeting (NT). Retro-orbital injections of P815 NT cells in syngeneic DBA/2 mice resulted in rapid development of aggressive SM within 13-16 days characterized by splenomegaly, extramedullary hematopoiesis, and multifocal liver tumors. In contrast, mice injected with P815 SHP2 KD cells showed less disease burden, including normal spleen weight and cellularity, and significant reductions in mastocytoma cells in spleen, bone marrow, peripheral blood and liver compared to NT controls. Treatment of human mast cell leukemia HMC-1 cells or P815 cells with SHP2 inhibitor II-B08, resulted in reduced colony formation and cell viability. Combining II-B08 with multi-kinase inhibitor Dasatinib showed enhanced efficacy than either inhibitor alone in blocking cell growth pathways and cell viability. Taken together, these results identify SHP2 as a key effector of oncogenic KIT and a therapeutic target in aggressive SM.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6; Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Namit
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6; Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Everingham
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, USA.
authors.forename: Li-Fan
authors.initials: LF
authors.lastname: Zeng
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, USA.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6; Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Andrew W B
authors.initials: AW
authors.lastname: Craig
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D000069439:Dasatinib / Q000494:pharmacology; D018450:Disease Progression; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D034721:Mastocytosis, Systemic / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology
chemical_list: C549053:3-(1-(3-(biphenyl-4-ylamino)-3-oxopropyl)-1H-1,2,3-triazol-4-yl)-6-hydroxy-1-methyl-2-phenyl-1H-indole-5-carboxylic acid; D007211:Indoles; D047428:Protein Kinase Inhibitors; D014230:Triazoles; D019009:Proto-Oncogene Proteins c-kit; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D000069439:Dasatinib