MEMBRANE SIALOGLYCOCONJUGATES AND SIALYLTRANSFERASES

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We have been investigating alterations in membrane glycoconjugates that may be related to the pathogenesis of chronic myelogenous leukemia (CML). We recently reported that CML cells show increased activity of a distinct about 2,3-sialyltransferase specific for O-linked Gal-Beta1,3-GalNAc acceptors and have also found evidence for hypersialylation of specific CML cell membrane glycoproteins. Our specific aims are: 1. To determine if the abnormal acceptor-specific sialyltransferase activity and hypersialylation of O-linked membrane glycoproteins are unique to PhI-positive CML. 2. To isolate and characterize the aberrant Gal-Beta 1,3-GalNAc-about 2,3-sialyltransferase from CML and normal leukocytes and determine whether its activity is stimulated by phosphorylation catalyzed by the altered oncogene product c-abl P210. 3. To determine whether hypersialylation of CML cell binding sites for factors that regulate myelopoiesis contributes to the proliferative advantage of CML versus normal granulocyte precursors in the bone marrow. 4. To explore whether chemotherapeutic agents that inhibit the synthesis or expression of membrane sialic acid may also reverse the hypersialylation and abnormal functioning of CML cells and thereby contribute to clinical treatment. These studies could yield important information about the pathophysiology of the myeloproliferative diseases, and could open new therapeutic possibilities for the better physiologic control of CML.