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Overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induced acute leukemia in p210BCR/ABL transgenic mice Mizuno, Toshiyuki Mizuno Toshiyuki Yamasaki, Norimasa Yamasaki Norimasa Miyazaki, Kazuko Miyazaki Kazuko Tazaki, Tatsuya Tazaki Tatsuya Koller, Richard Koller Richard Oda, Hideki Oda Hideki Honda, Zen-ichiro Honda Zen-ichiro Ochi, Mitsuo Ochi Mitsuo Wolff, Linda Wolff Linda Honda, Hiroaki Honda Hiroaki open access Copyright (c) 2008 Nature Publishing Group 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. Nature Publishing Group 2008-05 eng journal article AO https://hiroshima.repo.nii.ac.jp/records/2007899 10.1038/sj.onc.1211007 http://dx.doi.org/10.1038/sj.onc.1211007 0950-9232 AA10687380 Oncogene Oncogene 27 24 3465 3465 3474 https://hiroshima.repo.nii.ac.jp/record/2007899/files/Oncogene_27_3465.pdf 2.7 MB