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ID 26304
file
creator
Mizuno, Toshiyuki
Yamasaki, Norimasa
Miyazaki, Kazuko
Tazaki, Tatsuya
Koller, Richard
Oda, Hideki
Honda, Zen-ichiro
Wolff, Linda
subject
Chronic myelogenous leukemia
CML
blast crisis
BC
transgenic mice
Tg
p210BCR/ABL
Notch1
NDC
Medical sciences
abstract
Chronic myelogenous leukemia (CML) is a hematopoietic disorder, which begins as indolent chronic phase but inevitably progresses to fatal blast crisis. p210BCR/ABL, a constitutively active tyrosine kinase, is responsible for disease initiation but molecular mechanism(s) underlying disease evolution remains largely unknown. To explore this process, we employed retroviral insertional mutagenesis to CML-exhibiting p210BCR/ABL transgenic mice (Tg). Virus infection induced acute lymphoblastic leukemia (ALL) in p210BCR/ABL Tg with a higher frequency and in a shorter latency than wild-type littermates, and inverse PCR detected two retrovirus common integration sites (CISs) in p210BCR/ABL Tg tumors. Interestingly, one CIS was the transgene itself, where retrovirus integrations induced upregulation of p210BCR/ABL and production of truncated BCR/ABL with an enhanced kinase activity. Another CIS was Notch1 gene, where retrovirus integrations resulted in overexpression of Notch1 and generation of Notch1 lacking the C-terminal region (Notch1C) associated with stable expression of its activated product, C-terminus-truncated Notch intracellular domain (NICDC). In addition, generation of Tg for both p210BCR/ABL and Notch1C developed ALL in a shortened period with Stat5 activation, demonstrating the cooperative oncogenicity of Notch1C/NICDC with p210BCR/ABL involving Stat5-mediated pathway. These results demonstrated that overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induce acute leukemia in a transgenic model for CML.
journal title
Oncogene
volume
Volume 27
issue
Issue 24
start page
3465
end page
3474
date of issued
2008-05
publisher
Nature Publishing Group
issn
0950-9232
ncid
publisher doi
language
eng
nii type
Journal Article
HU type
Journal Articles
DCMI type
text
format
application/pdf
text version
author
rights
Copyright (c) 2008 Nature Publishing Group
relation is version of URL
http://dx.doi.org/10.1038/sj.onc.1211007
department
Graduate School of Biomedical Science
Research Institute for Radiation Biology and Medicine