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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2226-2232
NEOPLASIA
Reduced oncogenicity of p190
Bcr/Abl F-actin-binding domain mutants
Nora Heisterkamp,
Jan Willem Voncken,
Dinithi Senadheera,
Ignacio Gonzalez-Gomez,
Anja Reichert,
Leena Haataja,
Arja Reinikainen,
Paul K. Pattengale, and
John Groffen
From the Division of Hematology/Oncology, Section of
Molecular Carcinogenesis, and from the Department of Pathology,
Childrens Hospital of Los Angeles Research Institute, Los Angeles, CA.
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.
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