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

Oncogene

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.

Chronic myelogenous leukemia

CML

blast crisis

BC

transgenic mice

Tg

p210BCR/ABL

Notch1

Medical sciences [ 490 ]

eng

Nature Publishing Group

Copyright (c) 2008 Nature Publishing Group

[ISSN] 0950-9232

[DOI] 10.1038/sj.onc.1211007

[NCID] AA10687380

[DOI] http://dx.doi.org/10.1038/sj.onc.1211007 isVersionOf