2026-03-11T03:59:51Z https://hiroshima.repo.nii.ac.jp/oai

oai:hiroshima.repo.nii.ac.jp:02007899 2025-02-21T11:10:13Z 1730444907710

Overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induced acute leukemia in p210BCR/ABL transgenic mice Mizuno, Toshiyuki Yamasaki, Norimasa Miyazaki, Kazuko Tazaki, Tatsuya Koller, Richard Oda, Hideki Honda, Zen-ichiro Ochi, Mitsuo Wolff, Linda Honda, Hiroaki Chronic myelogenous leukemia CML blast crisis BC transgenic mice Tg p210BCR/ABL Notch1 490 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. http://purl.org/coar/resource_type/c_6501 Nature Publishing Group 2008-05 AO 0950-9232 AA10687380 3465 Oncogene 24 27 3474 3465 Oncogene https://hiroshima.repo.nii.ac.jp/records/2007899 eng 10.1038/sj.onc.1211007 http://dx.doi.org/10.1038/sj.onc.1211007 open access Copyright (c) 2008 Nature Publishing Group