The overall goal of our research has been to examine the molecular genetics of human myeloid leukemia. To this end we have studied two preleukemic syndromes chronic myelogenous leukemia (CML) and myelodysplasia (MDS). During our analysis of CML samples, we isolated a novel transforming gene in 2/8 patients. The molecular cloning and characterization of this gene, which we call axl, revealed that it is a novel receptor tyrosine kinase with subtle transforming activity and is localized to chromosome 19 where perturbations commonly occur in the progression to CML blast crisis. Preliminary data also suggests a role for axl in hematopoietic differentiation, especially towards the megakaryocytic lineage. We propose to expand our work on this novel oncogene by determining the genetic lesion that converts the normal axl to a transforming axl allele. We plan to raise antibodies to axl in order to better define its biochemical function, and to examine the role of this protein in human leukemias. Finally, we will pursue biological experiments to elucidate the function of axl in leukemogenesis and in hematopoietic differentiation. The results of our work will not only expand our understanding of a new class of receptor tyrosine kinases, but potentially will also provide clinicians with a new biochemical/genetic marker for leukemic progression and a new target for gene directed therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA049240-06
Application #
2093213
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1989-01-01
Project End
1996-04-30
Budget Start
1994-05-01
Budget End
1996-04-30
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Burchert, A; Attar, E C; McCloskey, P et al. (1998) Determinants for transformation induced by the Axl receptor tyrosine kinase. Oncogene 16:3177-87
Fridell, Y W; Villa Jr, J; Attar, E C et al. (1998) GAS6 induces Axl-mediated chemotaxis of vascular smooth muscle cells. J Biol Chem 273:7123-6
Fridell, Y W; Jin, Y; Quilliam, L A et al. (1996) Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase. Mol Cell Biol 16:135-45
O'Bryan, J P; Fridell, Y W; Koski, R et al. (1995) The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage. J Biol Chem 270:551-7
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Neubauer, A; Greenberg, P; Negrin, R et al. (1994) Mutations in the ras proto-oncogenes in patients with myelodysplastic syndromes. Leukemia 8:638-41
Neubauer, A; Fiebeler, A; Graham, D K et al. (1994) Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis. Blood 84:1931-41
McCloskey, P; Pierce, J; Koski, R A et al. (1994) Activation of the Axl receptor tyrosine kinase induces mitogenesis and transformation in 32D cells. Cell Growth Differ 5:1105-17
Neubauer, A; He, M; Schmidt, C A et al. (1993) Genetic alterations in the p53 gene in the blast crisis of chronic myelogenous leukemia: analysis by polymerase chain reaction based techniques. Leukemia 7:593-600

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