Gab2 is essential for Bcr-Abl mediated leukemic transformation and hydronephrosis in a chronic myeloid leukemia mouse model.
Halbach S, Köhler M, Uhl FM, Huber J, Zeiser R, Koschmieder S, Aumann K, Brummer T.
Bcr-Abl, the driver of chronic myeloid leukemia (CML), organizes its own signaling network. By being recruited to Bcr-Abl via Grb2, the docking protein Gab2 serves a critical role in this network. Earlier retroviral transduction experiments revealed an essential role of Gab2 for the transforming potential of Bcr-Abl. We showed previously that Gab2 expression is increased in human blast crisis samples and that high Gab2 levels protect CML cells from various tyrosine kinase inhibitors. Using a Gab2 knock-out allele, we have now analyzed the in vivo role of Gab2 in a CML model in which a tetracycline (Tet) regulated Bcr-Abl transgene is expressed in hematopoietic stem cells in their native microenvironment. We show for the first time that the Gab2 genotype has a profound effect on the course of the disease in a true in vivo setting. Our data invite for the further evaluation of Gab2 as a biomarker and as a valuable target in the treatment of CML.
