Early events in leukemogenesis in P190Bcr-abl transgenic mice.
The activated tyrosine kinase, Bcr-abl, is implicated in a number of hematopoietic malignancies. The exact biological mechanism by which the kinases transforms cells is still not well delineated. Previous data has suggested that the inhibition of apoptosis and the deregulation of cell cycle progression as the result of P210Bcr-abl expression might contribute to leukemogenesis. In vitro systems in which Bcr-Abl is over-expressed have concluded that similar growth regulatory pathways are affected as a result of the expression of both P210 and P190Bcr-abl. Here, we utilized an in vitro P190Bcr-abl leukemia mouse model to dissect the early events that contribute to transformation by this isoform of Bcr-Abl. In this mouse model P190Bcr-abl is expressed as a low but physiologically relevant level in that all mice develop pre-B leukemia lymphomas. We show that cell cycle and apoptotic responses to DNA damage are intact in bone marrow and spleen cells of such animals. We also demonstrate a normal induction of p21WAF-1/CIP1 in both hematopoietic and non-hematopoietic tissue as a result of genotoxic stress. We suggest that P190Bcr-abl induced transformation is different than that of P210Bcr-abl.
Salloukh
H F
HF
Department of Medicine, Division of Experimental Medicine, Royal Victoria Hospital, Hersey Pavilion (H5.21), 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1.
Vowles
I
I
Heisterkamp
N
N
Groffen
J
J
Laneuville
P
P
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D001853:Bone Marrow / Q000473:pathology / Q000502:physiology / Q000528:radiation effects; D017252:CD3 Complex / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007938:Leukemia / Q000235:genetics*; D008168:Lung / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011230:Precancerous Conditions; D013154:Spleen / Q000473:pathology / Q000502:physiology / Q000528:radiation effects; D014916:Whole-Body Irradiation
D000906:Antibodies; D017252:CD3 Complex; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007376:Interleukin-2; D016179:Granulocyte Colony-Stimulating Factor; D016044:Fusion Proteins, bcr-abl