2012 Fiscal Year Final Research Report
Therapeutic target of small GTPase for Ph positive leukemias
| Project/Area Number |
22591030
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
KUROSU Tetsuya 東京医科歯科大学, 医学部附属病院, 助教 (40361696)
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| Project Period (FY) |
2010 – 2012
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| Keywords | 血液腫瘍学 |
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| Research Abstract |
PECAM-1(CD31) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing surface glycoprotein expressed in various hematopoietic cells and plays roles in regulation of adhesion and migration of hematopoietic progenitor cells. PECAM-1 has also been implicated in activation of the Ras family GTPase Rap1 and in regulation of apoptosis. We previously reported that BCR/ABL activates the Rap1/B-Raf signaling pathway to regulate proliferation and integrin-mediated adhesion of Ph+ leukemic cells. In the present study, we demonstrate that PECAM-1 was tyrosine phosphorylated in ITIM in various BCR/ABL-expressing cells including primary CML and Ph+ ALL cells, which was inhibited by imatinib or dasatinib and was more prominently observed in cells expressing the imatinib-resistant E255K or T315I mutant. Transient expression experiments further revealed that ITIM in PECAM-1 was tyrosine phosphorylated by BCR/ABL or Lyn and was dephosphorylated by SHP2. Overexpression of PECAM-1 augmented BCR/ABL-mediated activation of Rap1/MEK/Erk pathway and enhanced chemotaxis induced by SDF-1, which also induced tyrosine phosphorylation of PECAM-1. Finally, PECAM-1 specifically inhibited apoptosis induced in K562 cells by imatinib or dasatinib but not that by the Bcl2 family antagonist ABT-737. These data suggest that PECAM-1 may play a role in regulation of apoptosis and migration of BCR/ABL-expressing cells to modulate their imatinib sensitivity and would be a possible candidate for therapeutic target in Ph+ leukemias.
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[Journal Article] Recurrenceof chronic active Epstein-Barr virus infection from donor cells after achieving complete response through allogeneic bone marrow transplantation2012
Author(s)
Arai A, Imadome K, Wang L, Wu N, Kurosu T, Wake A, Yamamoto H, Ota Y, Harigai M, Fujiwara S,Miura O
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Journal Title
Intern Med
Volume: 51(7)
Pages: 777-82
URL
Peer Reviewed
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