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

• Published in: Journal of cellular physiology Vol. 181; no. 3; pp. 433 - 447
• Main Authors: Augustine, Karen A., Rossi, Randall M., Van, Gwenyth, Housman, Jerry, Stark, Kevin, Danilenko, Dimitry, Varnum, Brian, Medlock, Eugene
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.12.1999
• Subjects: Animals; Base Sequence; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - immunology; Disease Models, Animal; DNA Primers - genetics; Gene Expression; Humans; Insulin Resistance; Islets of Langerhans - pathology; Leukemia, Myeloid - enzymology; Leukemia, Myeloid - genetics; Liver - pathology; Male; Mice; Mice, Transgenic; Oncogene Proteins - genetics; Phenotype; Proto-Oncogene Proteins; Rats; Receptor Protein-Tyrosine Kinases - genetics; Testis - pathology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/(SICI)1097-4652(199912)181:3<433::AID-JCP7>3.0.CO;2-Y

The axl tyrosine kinase receptor is aberrantly expressed on myeloid cells of many individuals afflicted with chronic myelogenous leukemia (CML) and other myeloid leukemias. Although previous studies demonstrated this kinase to have oncogenic potential, it is not known whether axl actively participates in the onset and/or progression of CML. We addressed this question by generating transgenic mice possessing constitutive ectopic expression of human 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 phenotypic characteristics associated with noninsulin‐dependent diabetes mellitus (NIDDM) including hyperglycemia and hyperinsulinemia, severe insulin resistance, progressive obesity, hepatic lipidosis, and pancreatic islet dysplasia. The obese‐diabetes phenotype was similar to that observed in the agouti 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 lipopolysaccharide (LPS) stimulation of peripheral blood. Administration of the axl 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 systemically expressed the gas6‐binding axl proteolytic cleavage product. A more severe NIDDM phenotype occurred in these mice. The observed phenotypes may be related to the axl receptor or proteolytic cleavage product competing with related axl family receptors for binding of the gas6 ligand. We conclude that axl expression in myeloid cells in itself does not lead to the onset or progression of leukemia and suggest that ectopic axl expression affects endogenous modulation of TNF‐alpha production indirectly resulting in the NIDDM phenotype. J. Cell. Physiol. 181:433–447, 1999. © 1999 Wiley‐Liss, Inc.