c-CBL is not required for leukemia induction by Bcr-Abl in mice.
Bcr-Abl tyrosine kinase activity is essential for the pathogenesis of chronic myeloid leukemia (CML). A number of Bcr-Abl substrates have been identified, but it is not clear which of these substrates are required for Bcr-Abl to transform cells. The multifunctional protein c-Cbl is one of the most prominently tyrosine-phosphorylated proteins in Bcr-Abl-expressing cells. Using cell lines and mice with homozygous disruption of the c-CBL locus, we investigated the role of this protein for Bcr-Abl-driven transformation. We find that although c-Cbl(-/-) fibroblast cell lines show a deficit in Bcr-Abl transformation compared to wild-type (Wt) cells, this deficit was less pronounced in c-Cbl(-/-) B cells derived from murine bone marrow. Most importantly, in a transplantation model of CML, Bcr-Abl was capable of inducing fatal leukemia in mice in the absence of c-Cbl protein. Our results indicate that c-Cbl is dispensable for Bcr-Abl-induced leukemogenesis in mice.
Dinulescu
Daniela M
DM
Department of Cell and Developmental Biology, OR, USA.
Wood
Lisa J
LJ
Shen
Lei
L
Loriaux
Marc
M
Corless
Christopher L
CL
Gross
Alec W
AW
Ren
Ruibao
R
Deininger
Michael W N
MW
Druker
Brian J
BJ
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases
D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D016044:Fusion Proteins, bcr-abl; C493849:Cbl protein, mouse