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.
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