PMID- 31203104
OWN - NLM
STAT- MEDLINE
DCOM- 20200520
LR  - 20200520
IS  - 1873-5835 (Electronic)
IS  - 0145-2126 (Linking)
VI  - 83
DP  - 2019 Aug
TI  - The upregulation of Pim kinases is essential in coordinating the survival, 
      proliferation, and migration of KIT D816V-mutated neoplastic mast cells.
PG  - 106166
LID - S0145-2126(19)30112-2 [pii]
LID - 10.1016/j.leukres.2019.106166 [doi]
AB  - About  80% of mast cell neoplasm patients harbor the c-Kit activating mutation 
      D816 V, which is associated with c-Kit inhibitor resistance and poor prognosis. 
      However, the molecular basis for these effects is not fully known. To address 
      this issue, in this study we screened molecules whose expression is altered by 
      KIT D816 V mutation and found that Pim kinases were overexpressed in D816V-mutant 
      neoplastic mast cells. This was accompanied by upregulation of signal transducer 
      and activator of transcription (STAT) and mammalian target of rapamycin (mTOR) 
      and downregulation of Akt and extracellular signal-regulated kinase (ERK1/2). 
      Activated Pim kinases promoted the survival of D816 V cells by maintaining mTOR 
      and p70S6K activation even under nutrient starvation. Conversely, cell 
      proliferation was suppressed by inhibiting Pim kinases. The mRNA level of C-X-C 
      chemokine receptor type 4 (CXCR4) was about 2-fold higher in D816 V cells; this 
      was associated with a 2-fold increase in migratory capacity, which was modulated 
      by Pim kinases. We also confirmed that upregulation of Pim kinases is a feature 
      specific to cells with the D816 V mutation and is not observed in cells with the 
      c-Kit activating N822 K mutation. These data suggest Pim kinases as a promising 
      therapeutic target for the treatment of mast cell neoplasms with KIT D816 V 
      mutation.
CI  - Copyright (c) 2019. Published by Elsevier Ltd.
FAU - Park, Hyejoo
AU  - Park H
AD  - Cancer Research Institute, Seoul National University College of Medicine, Seoul, 
      03080, Republic of Korea.
FAU - Kim, Dongchan
AU  - Kim D
AD  - Cancer Research Institute, Seoul National University College of Medicine, Seoul, 
      03080, Republic of Korea.
FAU - Koh, Youngil
AU  - Koh Y
AD  - Department of Internal Medicine, Seoul National University College of Medicine, 
      Seoul National University Hospital, Seoul, 03080, Republic of Korea.
FAU - Yoon, Sung-Soo
AU  - Yoon SS
AD  - Cancer Research Institute, Seoul National University College of Medicine, Seoul, 
      03080, Republic of Korea; Department of Internal Medicine, Seoul National 
      University College of Medicine, Seoul National University Hospital, Seoul, 03080, 
      Republic of Korea. Electronic address: ssysmc@snu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190612
PL  - England
TA  - Leuk Res
JT  - Leukemia research
JID - 7706787
RN  - EC 2.7.10.1 (KIT protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1)
RN  - EC 2.7.11.1 (proto-oncogene proteins pim)
SB  - IM
MH  - Amino Acid Substitution
MH  - Cell Line, Tumor
MH  - *Cell Movement
MH  - *Cell Proliferation
MH  - Cell Survival
MH  - *Gene Expression Regulation, Enzymologic
MH  - *Gene Expression Regulation, Leukemic
MH  - Humans
MH  - Leukemia, Mast-Cell/*enzymology/genetics/pathology
MH  - *MAP Kinase Signaling System
MH  - *Mutation, Missense
MH  - Proto-Oncogene Proteins c-kit/*biosynthesis/genetics
MH  - Proto-Oncogene Proteins c-pim-1/*biosynthesis/genetics
MH  - *Up-Regulation
OTO - NOTNLM
OT  - Cell migration
OT  - Cell survival
OT  - KITD816V
OT  - Mast cell neoplasm
OT  - Pim kinase
EDAT- 2019/06/17 06:00
MHDA- 2020/05/21 06:00
CRDT- 2019/06/17 06:00
PHST- 2019/03/29 00:00 [received]
PHST- 2019/05/19 00:00 [revised]
PHST- 2019/06/06 00:00 [accepted]
PHST- 2019/06/17 06:00 [pubmed]
PHST- 2020/05/21 06:00 [medline]
PHST- 2019/06/17 06:00 [entrez]
AID - S0145-2126(19)30112-2 [pii]
AID - 10.1016/j.leukres.2019.106166 [doi]
PST - ppublish
SO  - Leuk Res. 2019 Aug;83:106166. doi: 10.1016/j.leukres.2019.106166. Epub 2019 Jun 
      12.