Total proteome analysis identifies migration defects as a major pathogenetic factor in immunoglobulin heavy chain variable region (IGHV)-unmutated chronic lymphocytic leukemia.
Bottom Line: Furthermore, UM-CLL cells underexpressed proteins associated with cytoskeletal remodeling and overexpressed proteins associated with transcriptional and translational activity.Taken together, our findings indicate that UM-CLL cells are less migratory and more adhesive than M-CLL cells, resulting in their retention in lymph nodes, where they are exposed to proliferative stimuli.Our study illustrates the potential of total proteome analysis to elucidate pathogenetic mechanisms in cancer.
Affiliation: From the ‡Department of Molecular and Clinical Cancer Medicine.Show MeSH
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Mentions: The lymphocyte chemotaxis pathway, which is essential for migration into and transit within lymphoid tissues (34), was significantly altered (p < 0.001) in UM-CLL cells. Of particular note, eight of the nine differentially expressed proteins in this pathway were expressed at significantly lower levels in UM-CLL samples (Fig. 3). These underexpressed proteins included the Rap (Ras-related protein) activator CalDAG-GEFI (RAS guanyl-releasing protein 2; Q7LDG7), which is involved in integrin activation (35, 36); both chains of the αLβ2 integrin (P20701 and P05107), which is required for the migration of lymphocytes into lymph nodes; and talin (Q9Y490), which is important in maintaining the high-affinity binding state of αLβ2 (37). Collectively, these observations strongly suggest that UM-CLL is associated with impaired Rap1-dependent αLβ2-mediated migration.
Affiliation: From the ‡Department of Molecular and Clinical Cancer Medicine.