C-Abl’s Roles In Mouse Gastrointestinal Homeostasis

Imatinib Mesylate is used to treat chronic myeloid leukemia and a number of othercancers and its main targets include Abl kinases, c-Kit, and PDGFR. Here we report thattreatment of normal mice with Imatinib Mesylate led to defects in the muscle layers of theesophagus, stomach, and large intestines, revealing an adverse side effect of the drug.Adult mouse deficient for proto-oncogene c-Abl showed similar defects in thegastrointestinal tract, especially the muscularis propria, suggesting that Imatinib Mesylatemay influence gastrointestinal homeostasis by targeting c-Abl. Moreover, at advanced ages,c-Abl^-/-mice showed megaesophagus and rectal prolapse that are likely caused by defectsin the muscularis propria. Pathogenesis of megaesophagus may involve the plasminogensystem, which is inhibited by c-Abl deficiency. Although deficiency of pro-aging genep16^Ink4Apartially rescued perinatal lethality and reproduction defects of c-Abl^-/-mice, itshowed no effect on megaesophagus and a very modest effect on rectal prolapse,suggesting that these two disorders may have little contribution from p16^Ink4A-mediatedaging. These resμLts indicate that c-Abl^-/-mice present a model useful for studying thepathogenesis of megaesophagus and rectal prolapse and imply that use of ImatinibMesylate may cause gastrointestinal problems in patients.