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Total proteome analysis identifies migration defects as a major pathogenetic factor in immunoglobulin heavy chain variable region (IGHV)-unmutated chronic lymphocytic leukemia.

Eagle GL, Zhuang J, Jenkins RE, Till KJ, Jithesh PV, Lin K, Johnson GG, Oates M, Park K, Kitteringham NR, Pettitt AR - Mol. Cell Proteomics (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: From the ‡Department of Molecular and Clinical Cancer Medicine.

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Related in: MedlinePlus

Schematic diagram illustrating factors involved in lymphocyte migration into, retention within, and egress from lymph nodes. Migration into, within, and through lymphoid tissues is a complex multistep process. The major steps are illustrated here, along with the pathways/proteins that are altered in UM-CLL versus M-CLL. On initial contact with the endothelium, the lymphocytes become loosely tethered (A). If the cell encounters chemokine presented on the endothelial cell surface, it then becomes firmly adherent in a process involving integrin activation and chemokine signaling (B). The cell then crawls along the endothelium until it reaches an intercellular junction, where it undergoes diapedesis in response to chemokine (C); this process also requires integrin activation. Once within the lymphoid tissue (D), two different mechanisms mediate the adherence of CLL cells within the tissues; these involve α4β1 and CD44 binding to their respective ligands, fibronectin and hyaluronan. Adhesion mediated by both substrata is influenced by chemokine signaling. The final step of transit though the lymph node is egress (E), a process that is entirely dependent on S1PR1 and is independent of integrins.
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Figure 2: Schematic diagram illustrating factors involved in lymphocyte migration into, retention within, and egress from lymph nodes. Migration into, within, and through lymphoid tissues is a complex multistep process. The major steps are illustrated here, along with the pathways/proteins that are altered in UM-CLL versus M-CLL. On initial contact with the endothelium, the lymphocytes become loosely tethered (A). If the cell encounters chemokine presented on the endothelial cell surface, it then becomes firmly adherent in a process involving integrin activation and chemokine signaling (B). The cell then crawls along the endothelium until it reaches an intercellular junction, where it undergoes diapedesis in response to chemokine (C); this process also requires integrin activation. Once within the lymphoid tissue (D), two different mechanisms mediate the adherence of CLL cells within the tissues; these involve α4β1 and CD44 binding to their respective ligands, fibronectin and hyaluronan. Adhesion mediated by both substrata is influenced by chemokine signaling. The final step of transit though the lymph node is egress (E), a process that is entirely dependent on S1PR1 and is independent of integrins.

Mentions: We next used GeneGo pathway maps from MetaCore to identify pathways enriched by the 274 proteins that were differentially expressed in the two subsets of CLL samples (p < 0.05). The enrichment analysis identified 169 signaling pathways (p < 0.05) (supplemental Table S3). Remarkably, 26 of the top 50 most significantly altered pathways were associated with cell migration/adhesion. In total, 43 cell migration/adhesion pathways (Table 2) were significantly enriched by 39 differentially expressed proteins (Table 3). As all of these 39 proteins were involved in lymphocyte entry into, transit within, or exit from the lymphoid tissues (Fig. 2) and 35 of them were expressed at significantly lower levels in UM-CLL samples, these results suggest that UM-CLL cells have reduced migratory properties compared with their M-CLL counterparts.


Total proteome analysis identifies migration defects as a major pathogenetic factor in immunoglobulin heavy chain variable region (IGHV)-unmutated chronic lymphocytic leukemia.

Eagle GL, Zhuang J, Jenkins RE, Till KJ, Jithesh PV, Lin K, Johnson GG, Oates M, Park K, Kitteringham NR, Pettitt AR - Mol. Cell Proteomics (2015)

Schematic diagram illustrating factors involved in lymphocyte migration into, retention within, and egress from lymph nodes. Migration into, within, and through lymphoid tissues is a complex multistep process. The major steps are illustrated here, along with the pathways/proteins that are altered in UM-CLL versus M-CLL. On initial contact with the endothelium, the lymphocytes become loosely tethered (A). If the cell encounters chemokine presented on the endothelial cell surface, it then becomes firmly adherent in a process involving integrin activation and chemokine signaling (B). The cell then crawls along the endothelium until it reaches an intercellular junction, where it undergoes diapedesis in response to chemokine (C); this process also requires integrin activation. Once within the lymphoid tissue (D), two different mechanisms mediate the adherence of CLL cells within the tissues; these involve α4β1 and CD44 binding to their respective ligands, fibronectin and hyaluronan. Adhesion mediated by both substrata is influenced by chemokine signaling. The final step of transit though the lymph node is egress (E), a process that is entirely dependent on S1PR1 and is independent of integrins.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4390271&req=5

Figure 2: Schematic diagram illustrating factors involved in lymphocyte migration into, retention within, and egress from lymph nodes. Migration into, within, and through lymphoid tissues is a complex multistep process. The major steps are illustrated here, along with the pathways/proteins that are altered in UM-CLL versus M-CLL. On initial contact with the endothelium, the lymphocytes become loosely tethered (A). If the cell encounters chemokine presented on the endothelial cell surface, it then becomes firmly adherent in a process involving integrin activation and chemokine signaling (B). The cell then crawls along the endothelium until it reaches an intercellular junction, where it undergoes diapedesis in response to chemokine (C); this process also requires integrin activation. Once within the lymphoid tissue (D), two different mechanisms mediate the adherence of CLL cells within the tissues; these involve α4β1 and CD44 binding to their respective ligands, fibronectin and hyaluronan. Adhesion mediated by both substrata is influenced by chemokine signaling. The final step of transit though the lymph node is egress (E), a process that is entirely dependent on S1PR1 and is independent of integrins.
Mentions: We next used GeneGo pathway maps from MetaCore to identify pathways enriched by the 274 proteins that were differentially expressed in the two subsets of CLL samples (p < 0.05). The enrichment analysis identified 169 signaling pathways (p < 0.05) (supplemental Table S3). Remarkably, 26 of the top 50 most significantly altered pathways were associated with cell migration/adhesion. In total, 43 cell migration/adhesion pathways (Table 2) were significantly enriched by 39 differentially expressed proteins (Table 3). As all of these 39 proteins were involved in lymphocyte entry into, transit within, or exit from the lymphoid tissues (Fig. 2) and 35 of them were expressed at significantly lower levels in UM-CLL samples, these results suggest that UM-CLL cells have reduced migratory properties compared with their M-CLL counterparts.

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.

View Article: PubMed Central - PubMed

Affiliation: From the ‡Department of Molecular and Clinical Cancer Medicine.

Show MeSH
Related in: MedlinePlus