PMID- 15085152
OWN - NLM
STAT- MEDLINE
DCOM- 20040623
LR  - 20191210
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 18
IP  - 6
DP  - 2004 Jun
TI  - Constitutively activated phosphatidylinositol 3-kinase primes platelets from 
      patients with chronic myelogenous leukemia for thrombopoietin-induced 
      aggregation.
PG  - 1127-37
AB  - In this study, we examined the effect of thrombopoietin (TPO) on the aggregation 
      of platelets from 40 patients with myeloproliferative disorders (MPDs), including 
      17 patients with chronic myelogenous leukemia in the chronic phase (CML-CP), 10 
      with polycythemia vera, 10 with essential thrombocythemia, and three with 
      myelofibrosis. TPO by itself dose-dependently induced the aggregation of 
      platelets from patients with CML-CP but not from those with other MPDs or with 
      CML-CP in cytogenetical complete remission. The expression of CD63 in CML-CP 
      platelets was induced by TPO treatment. Phosphatidylinositol 3-kinase 
      (PI3-kinase) was constitutively activated in CML-CP platelets. Pretreatment with 
      PI3-kinase inhibitors (wortmannin and LY294002) dose-dependently inhibited 
      TPO-induced aggregation of CML-CP platelets. The Abl kinase inhibitor imatinib 
      mesylate and the Jak inhibitor AG490 suppressed TPO-induced aggregation of CML-CP 
      platelets. Pretreatment with imatinib mesylate, but not with AG490, inhibited the 
      activity of PI3-kinase in CML-CP platelets. In addition, tyrosine phosphorylation 
      of Jak2 was undetected in CML-CP platelets before TPO treatment. These findings 
      indicate that the constitutive activation of PI3-kinase primes CML-CP platelets 
      for the aggregation induced by TPO, and that Bcr-Abl, but not Jak family protein 
      tyrosine kinases, are involved in the constitutive activation of PI3-kinase in 
      CML-CP platelets.
FAU - Kubota, Y
AU  - Kubota Y
AD  - The Department of Transfusion Medicine, Faculty of Medicine, Kagawa University, 
      Kagawa, Japan. yokubota@kms.ac.jp
FAU - Tanaka, T
AU  - Tanaka T
FAU - Ohnishi, H
AU  - Ohnishi H
FAU - Kitanaka, A
AU  - Kitanaka A
FAU - Okutani, Y
AU  - Okutani Y
FAU - Taminato, T
AU  - Taminato T
FAU - Ishida, T
AU  - Ishida T
FAU - Kamano, H
AU  - Kamano H
LA  - eng
PT  - Journal Article
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Androstadienes)
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 42HK56048U (Tyrosine)
RN  - 9014-42-0 (Thrombopoietin)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Blood Platelets/*enzymology
MH  - Chromones/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation/physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - In Vitro Techniques
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*metabolism
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Platelet Aggregation/*drug effects/physiology
MH  - Thrombopoietin/*pharmacology
MH  - Tyrosine/metabolism
MH  - Wortmannin
EDAT- 2004/04/16 05:00
MHDA- 2004/06/24 05:00
CRDT- 2004/04/16 05:00
PHST- 2004/04/16 05:00 [pubmed]
PHST- 2004/06/24 05:00 [medline]
PHST- 2004/04/16 05:00 [entrez]
AID - 2403370 [pii]
AID - 10.1038/sj.leu.2403370 [doi]
PST - ppublish
SO  - Leukemia. 2004 Jun;18(6):1127-37. doi: 10.1038/sj.leu.2403370.