BCR/ABL P190 transgenic mice develop leukemia in the absence of Crkl.
The Bcr/Abl fusion protein directly causes chronic myelogenous leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia. Multiple independent studies have implicated Crkl, a small adapter protein, in transduction of oncogenic signals of Bcr/Abl and Crkl tyrosine-phosphorylation is used as a diagnostic tool for Philadelphia-positive leukemia. To evaluate the contribution of Crkl to this type of leukemia, we generated mutant mice that lack Crkl expression. We found that the overall survival of P190 BCR/ABL crkl-/- mice was comparable to that of genetically matched P190 BCR/ABL crkl +/+ mice. Both genotypes developed lymphoid lineage leukemia/lymphoma. Western blot analysis of -/- and +/+ lymphomas showed that the related Crk protein was tyrosine phosphorylated and could be found complexed with Bcr-Abl P190. These data indicate that possible therapeutic approaches that target Crkl may be complicated by the presence of pathways that compensate for lack of Crkl function.
Hemmeryckx
Bianca
B
Section of Molecular Carcinogenesis, Division of Hematology/Oncology, Ms #54, Childrens Hospital of Los Angeles Research Institute, and the Keck School of Medicine-University of Southern California, Los Angeles, CA 90027, USA.
Reichert
Anja
A
Watanabe
Meguru
M
Kaartinen
Vesa
V
de Jong
Ron
R
Pattengale
Paul K
PK
Groffen
John
J
Heisterkamp
Nora
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015195:Drug Design; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics*; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D050737:Proto-Oncogene Proteins c-crk; D015398:Signal Transduction / Q000502:physiology
D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D016044:Fusion Proteins, bcr-abl