Overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induced acute leukemia in p210BCR/ABL transgenic mice.
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 (Notch1DeltaC) associated with stable expression of its activated product, C-terminal-truncated Notch intracellular domain (NICD Delta C). In addition, generation of Tg for both p210BCR/ABL and Notch1DeltaC developed ALL in a shortened period with Stat5 activation, demonstrating the cooperative oncogenicity of Notch1DeltaC/NICD Delta C with p210BCR/ABL involving Stat5-mediated pathway. These results demonstrated that overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induces acute leukemia in a transgenic model for CML.
Mizuno
T
T
Department of Developmental Biology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Yamasaki
N
N
Miyazaki
K
K
Tazaki
T
T
Koller
R
R
Oda
H
H
Honda
Z-i
ZI
Ochi
M
M
Wolff
L
L
Honda
H
H
D000818:Animals; D000831:Animals, Newborn; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008980:Moloney murine sarcoma virus / Q000472:pathogenicity; D016254:Mutagenesis, Insertional / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D012190:Retroviridae / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015996:Survival Rate; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016662:Virus Integration / Q000502:physiology*
C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D050799:STAT5 Transcription Factor; D016044:Fusion Proteins, bcr-abl