PMID- 30864683
OWN - NLM
STAT- MEDLINE
DCOM- 20190813
LR  - 20190813
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 54
IP  - 5
DP  - 2019 May
TI  - TOPK is regulated by PP2A and BCR/ABL in leukemia and enhances cell 
      proliferation.
PG  - 1785-1796
LID - 10.3892/ijo.2019.4740 [doi]
AB  - Although treatment of chronic myeloid leukemia (CML) has improved with the 
      development of tyrosine kinase inhibitors (TKIs), patients develop fatal blast 
      crisis (BC) whilst receiving TKI treatment. Alternative treatments for cases 
      resistant to TKIs are required. A serine/threonine protein kinase, 
      T‑lymphokine‑activated killer cell‑originated protein kinase (TOPK), is highly 
      expressed in various malignant tumors. Binding of peptides to human leukocyte 
      antigen was assessed via mass spectrometry in K562 CML cells. TOPK expression was 
      assessed in various CML cell lines and in clinical samples obtained from patients 
      with CML using reverse transcription‑quantitative polymerase chain reaction and 
      western blot assays. It was observed that TOPK was expressed abundantly in 
      BCR/ABL‑positive cell lines and at significantly higher levels in CML clinical 
      samples compared with healthy donor samples. Overexpression of BCR/ABL or the 
      presence of its inhibitor imatinib upregulated and downregulated TOPK expression, 
      respectively, indicating that TOPK may be a target of BCR/ABL. TOPK inhibitor 
      OTS514 suppressed proliferation of BCR/ABL‑positive cell lines and colony 
      formation of CD34‑positive cells from patients with CML compared with lymphoma 
      patients without bone marrow involvement. Furthermore, phosphorylation of TOPK 
      was increased by protein phosphatase 2A (PP2A) inhibitor okadaic acid and was 
      decreased in the presence of PP2A activator FTY720 compared with untreated 
      samples. As constitutive BCR/ABL activity and inhibition of PP2A are key 
      mechanisms of CML development, TOPK may be a crucial signaling molecule for this 
      disease. Inhibition of TOPK may control disease status of CML, even in cases 
      resistant to TKIs.
FAU - Uchida, Emi
AU  - Uchida E
AD  - Department of Hematology, Tokyo Medical and Dental University, Tokyo 113‑8519, 
      Japan.
FAU - Suwa, Shihoko
AU  - Suwa S
AD  - Department of Hematology, Tokyo Medical and Dental University, Tokyo 113‑8519, 
      Japan.
FAU - Yoshimoto, Ryoto
AU  - Yoshimoto R
AD  - Department of Hematology, Tokyo Medical and Dental University, Tokyo 113‑8519, 
      Japan.
FAU - Watanabe, Ken
AU  - Watanabe K
AD  - Department of Hematology, Tokyo Medical and Dental University, Tokyo 113‑8519, 
      Japan.
FAU - Kasama, Takeshi
AU  - Kasama T
AD  - Research Center for Medical and Dental Sciences, Tokyo Medical and Dental 
      University, Tokyo 113‑8519, Japan.
FAU - Miura, Osamu
AU  - Miura O
AD  - Department of Hematology, Tokyo Medical and Dental University, Tokyo 113‑8519, 
      Japan.
FAU - Fukuda, Tetsuya
AU  - Fukuda T
AD  - Department of Hematology, Tokyo Medical and Dental University, Tokyo 113‑8519, 
      Japan.
LA  - eng
PT  - Journal Article
DEP - 20190305
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (HLA-A24 Antigen)
RN  - 0 (OTS514)
RN  - 0 (Quinolones)
RN  - 0 (Thiophenes)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 2.7.12.2 (PDZ-binding kinase)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Blast Crisis/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Female
MH  - Fusion Proteins, bcr-abl/genetics/*metabolism
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - HLA-A24 Antigen/genetics/metabolism
MH  - Humans
MH  - Imatinib Mesylate/pharmacology
MH  - K562 Cells
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/metabolism/*pathology
MH  - Male
MH  - Middle Aged
MH  - Mitogen-Activated Protein Kinase Kinases/genetics/*metabolism
MH  - Phosphorylation
MH  - Protein Phosphatase 2/genetics/*metabolism
MH  - Quinolones/pharmacology
MH  - Thiophenes/pharmacology
MH  - Young Adult
EDAT- 2019/03/14 06:00
MHDA- 2019/08/14 06:00
CRDT- 2019/03/14 06:00
PHST- 2018/08/10 00:00 [received]
PHST- 2019/01/21 00:00 [accepted]
PHST- 2019/03/14 06:00 [pubmed]
PHST- 2019/08/14 06:00 [medline]
PHST- 2019/03/14 06:00 [entrez]
AID - 10.3892/ijo.2019.4740 [doi]
PST - ppublish
SO  - Int J Oncol. 2019 May;54(5):1785-1796. doi: 10.3892/ijo.2019.4740. Epub 2019 Mar 
      5.