PMID- 25026279
OWN - NLM
STAT- MEDLINE
DCOM- 20151221
LR  - 20211021
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 5
IP  - 15
DP  - 2014 Aug 15
TI  - Oncogenic KIT-induced aggressive systemic mastocytosis requires SHP2/PTPN11 
      phosphatase for disease progression in mice.
PG  - 6130-41
AB  - 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.
FAU - Sharma, Namit
AU  - Sharma N
AD  - 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.
FAU - Everingham, Stephanie
AU  - Everingham S
AD  - 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.
FAU - Zeng, Li-Fan
AU  - Zeng LF
AD  - Department of Biochemistry and Molecular Biology, Indiana University, 
      Indianapolis, IN, USA.
FAU - Zhang, Zhong-Yin
AU  - Zhang ZY
AD  - Department of Biochemistry and Molecular Biology, Indiana University, 
      Indianapolis, IN, USA.
FAU - Kapur, Reuben
AU  - Kapur R
AD  - 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.
FAU - Craig, Andrew W B
AU  - Craig AW
AD  - 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.
LA  - eng
GR  - R01 HL081111/HL/NHLBI NIH HHS/United States
GR  - R01 CA173852/CA/NCI NIH HHS/United States
GR  - R01 CA134777/CA/NCI NIH HHS/United States
GR  - R01CA173852/CA/NCI NIH HHS/United States
GR  - R01CA134777/CA/NCI NIH HHS/United States
GR  - R01HL081111/HL/NHLBI NIH HHS/United States
GR  - R01 HL077177/HL/NHLBI NIH HHS/United States
GR  - R01 CA152194/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 
      (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)
RN  - 0 (Indoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Triazoles)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
RN  - RBZ1571X5H (Dasatinib)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology
MH  - Apoptosis/physiology
MH  - Cell Proliferation/physiology
MH  - Dasatinib/pharmacology
MH  - Disease Progression
MH  - Drug Synergism
MH  - Humans
MH  - Indoles/pharmacology
MH  - Mastocytosis, Systemic/drug therapy/*enzymology/pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & 
      inhibitors/*metabolism
MH  - Proto-Oncogene Proteins c-kit/*metabolism
MH  - Signal Transduction
MH  - Triazoles/pharmacology
PMC - PMC4171618
COIS- The authors declare no conflict of interest.
EDAT- 2014/07/16 06:00
MHDA- 2015/12/22 06:00
PMCR- 2014/08/01
CRDT- 2014/07/16 06:00
PHST- 2014/07/16 06:00 [entrez]
PHST- 2014/07/16 06:00 [pubmed]
PHST- 2015/12/22 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - 2177 [pii]
AID - 10.18632/oncotarget.2177 [doi]
PST - ppublish
SO  - Oncotarget. 2014 Aug 15;5(15):6130-41. doi: 10.18632/oncotarget.2177.