The Bcr N-terminal oligomerization domain contributes to the full oncogenicity of P190 Bcr/Abl in transgenic mice.
The Bcr/Abl P190 oncoprotein is responsible for the development of Philadelphia-chromosome positive acute lymphoblastic leukemia (ALL). The Bcr moiety in Bcr/Abl activates the Abl tyrosine kinase, an ingredient essential for the transforming capability of Bcr/Abl. Residues 1-63 of Bcr form an N-terminal oligomerization domain and are key to Abl activation in vitro. Mice transgenic for P190 BCR/ABL reproducibly develop an aggressive B-lineage lymphoblastic leukemia/lymphoma. Here we test the hypothesis that residues 1-63 of Bcr have a major in vivo contribution to the oncogenicity of Bcr/Abl P190 by the generation of mice transgenic for an N-terminal deleted form of P190. We find that although the transgene is expressed in the bone marrow of mice at an early age, the incidence of leukemogenesis is greatly diminished as compared to mice transgenic for non-mutated P190 Bcr/Abl. Sporadic hematological malignancies which did develop showed decreased levels of phosphotyrosine as compared to those of wild-type P190 transgenics, although Ras was activated. These results demonstrate that the Bcr oligomerization domain contributes to the oncogenicity of Bcr/Abl in vivo.
Heisterkamp
N
N
Division of Hematology/Oncology, Ms#54, Section of Molecular Carcinogenesis, Childrens Hospital of Los Angeles Research Institute, Los Angeles, CA 90027, USA. heisterk@hsc.usc.edu
Voncken
J W
JW
Senadheera
D
D
Hemmeryckx
B
B
Gonzalez-Gomez
I
I
Reichert
A
A
Pattengale
P K
PK
Groffen
J
J
D000818:Animals; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D007942:Leukemia, Experimental / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051562:Proto-Oncogene Proteins c-bcr; D017384:Sequence Deletion
D015513:Oncogene Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr