Reduced oncogenicity of p190 Bcr/Abl F-actin-binding domain mutants.
The deregulated Bcr/Abl tyrosine kinase is responsible for the development of Philadelphia (Ph)-positive leukemia in humans. To investigate the significance of the C-terminal Abl actin-binding domain within Bcr/Abl p190 in the development of leukemia/lymphoma in vivo, mutant p190 DNA constructs were used to generate transgenic mice. Eight founder and progeny mice of 5 different lines were monitored for leukemogenesis. Latency was markedly increased and occurrence decreased in the p190 del C lines as compared with nonmutated p190 BCR/ABL transgenics. Western blot analysis of involved hematologic tissues of the p190 del C transgenics with end-stage disease showed high-level expression of the transgene and tyrosine phosphorylation of Cbl and Hef1/Cas, proteins previously shown to be affected by Bcr/Abl. These results show that the actin-binding domain of Abl enhances leukemia development but does not appear to be an absolute requirement for leukemogenesis.
Heisterkamp
N
N
Division of Hematology/Oncology, Section of Molecular Carcinogenesis, and from the Department of Pathology, Childrens Hospital of Los Angeles Research Institute, Los Angeles, CA 90027, USA. heisterk@hsc.usc.edu
Voncken
J W
JW
Senadheera
D
D
Gonzalez-Gomez
I
I
Reichert
A
A
Haataja
L
L
Reinikainen
A
A
Pattengale
P K
PK
Groffen
J
J
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding
D000199:Actins; D016044:Fusion Proteins, bcr-abl