Noninsulin-dependent diabetes mellitus occurs in mice ectopically expressing the human axl tyrosine kinase receptor

The axl tyrosine kinase receptor is aberrantly expressed on myeloid cells o f many individuals afflicted with chronic myelogenous leukemia (CML) and ot her myeloid leukemias. Although previous studies demonstrated this kinase t o have oncogenic potential, it is not known whether axl actively participat es in the onset and/or progression of CML. We addressed this question by ge nerating transgenic mice possessing constitutive ectopic expression of huma n axl throughout cells of the myeloid hematopoietic lineage through the use of the granulocyte colony-stimulating factor (GCSF) receptor promoter. The transgenics did not exhibit hematopoietic malignancies, but did exhibit ph enotypic characteristics associated with noninsulin-dependent diabetes mell itus (NIDDM) including hyperglycemia and hyperinsulinemia, severe insulin r esistance, progressive obesity, hepatic lipidosis, and pancreatic islet dys plasia. The obese-diabetes phenotype was similar to that observed in the ag outi and melanocortin-4(-/-) mutants, however the axl transgenics were not hyperphagic. Axl transgenic animals expressed elevated serum tumor necrosis factor (TNF)-alpha levels that were further enhanced upon in vitro lipopol ysaccharide (LPS) stimulation of peripheral blood. Administration of the ax l ligand, gas6, to peripheral transgenic blood samples eliminated excessive TNF-alpha production in response to LPS stimulation. As a means to better understand axl-gas6 biology, transgenic animals were produced which systemi cally expressed the gas6-binding axl proteolytic cleavage product. A more s evere NIDDM phenotype occurred in these mice. The observed phenotypes may b e related to the axl receptor or proteolytic cleavage product competing wit h related axl family receptors for binding of the gas6 ligand. We conclude chat axl expression in myeloid cells in itself does not lead to the onset o r progression of leukemia and suggest that ectopic axl expression affects e ndogenous modulation of TNF-alpha production indirectly resulting in the NI DDM phenotype. (C) 1999 Wiley-Liss, Inc.