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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

Enrichment of leukocyte chemotaxis pathway by proteins found to be differentially expressed in M-CLL versus UM-CLL. One of the migration pathways most enriched by the GeneGo MetaCore pathway maps using proteins differentially expressed between UM-CLL and M-CLL was the leukocyte chemotaxis pathway (p < 0.001). This pathway directs leukocyte movement to lymphatic organs and also allows them to migrate to sites of infection and/or inflammation via either αLβ2 or α4β1 integrins (highlighted). Within this pathway, nine proteins were found to be differentially expressed: MHC class II (P20036, p = 0.02), G-protein αi family (P04899, p = 0.006), CalDAG-GEFI (Q7LDG7, p = 0.006), ARF6 (P62330, p = 0.013), actin (P68032, p = 0.011), actin cytoskeletal (P63261, p = 0.014), talin (Q9Y490, p = 0.015), ITGB2 (P05107, p = 0.046), and αLβ2 (P20701, p = 0.023; P05107, p = 0.046). MHC class II had a higher expression in UM-CLL (fold changes represented by a red thermometer). However, the other eight differentially expressed proteins had a lower expression in UM-CLL (fold changes represented by blue thermometers) compared with M-CLL. This suggests that migration into the tissue microenvironments via the αLβ2 integrin pathway may be dysfunctional in UM-CLL.
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Figure 3: Enrichment of leukocyte chemotaxis pathway by proteins found to be differentially expressed in M-CLL versus UM-CLL. One of the migration pathways most enriched by the GeneGo MetaCore pathway maps using proteins differentially expressed between UM-CLL and M-CLL was the leukocyte chemotaxis pathway (p < 0.001). This pathway directs leukocyte movement to lymphatic organs and also allows them to migrate to sites of infection and/or inflammation via either αLβ2 or α4β1 integrins (highlighted). Within this pathway, nine proteins were found to be differentially expressed: MHC class II (P20036, p = 0.02), G-protein αi family (P04899, p = 0.006), CalDAG-GEFI (Q7LDG7, p = 0.006), ARF6 (P62330, p = 0.013), actin (P68032, p = 0.011), actin cytoskeletal (P63261, p = 0.014), talin (Q9Y490, p = 0.015), ITGB2 (P05107, p = 0.046), and αLβ2 (P20701, p = 0.023; P05107, p = 0.046). MHC class II had a higher expression in UM-CLL (fold changes represented by a red thermometer). However, the other eight differentially expressed proteins had a lower expression in UM-CLL (fold changes represented by blue thermometers) compared with M-CLL. This suggests that migration into the tissue microenvironments via the αLβ2 integrin pathway may be dysfunctional in UM-CLL.

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.


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)

Enrichment of leukocyte chemotaxis pathway by proteins found to be differentially expressed in M-CLL versus UM-CLL. One of the migration pathways most enriched by the GeneGo MetaCore pathway maps using proteins differentially expressed between UM-CLL and M-CLL was the leukocyte chemotaxis pathway (p < 0.001). This pathway directs leukocyte movement to lymphatic organs and also allows them to migrate to sites of infection and/or inflammation via either αLβ2 or α4β1 integrins (highlighted). Within this pathway, nine proteins were found to be differentially expressed: MHC class II (P20036, p = 0.02), G-protein αi family (P04899, p = 0.006), CalDAG-GEFI (Q7LDG7, p = 0.006), ARF6 (P62330, p = 0.013), actin (P68032, p = 0.011), actin cytoskeletal (P63261, p = 0.014), talin (Q9Y490, p = 0.015), ITGB2 (P05107, p = 0.046), and αLβ2 (P20701, p = 0.023; P05107, p = 0.046). MHC class II had a higher expression in UM-CLL (fold changes represented by a red thermometer). However, the other eight differentially expressed proteins had a lower expression in UM-CLL (fold changes represented by blue thermometers) compared with M-CLL. This suggests that migration into the tissue microenvironments via the αLβ2 integrin pathway may be dysfunctional in UM-CLL.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Enrichment of leukocyte chemotaxis pathway by proteins found to be differentially expressed in M-CLL versus UM-CLL. One of the migration pathways most enriched by the GeneGo MetaCore pathway maps using proteins differentially expressed between UM-CLL and M-CLL was the leukocyte chemotaxis pathway (p < 0.001). This pathway directs leukocyte movement to lymphatic organs and also allows them to migrate to sites of infection and/or inflammation via either αLβ2 or α4β1 integrins (highlighted). Within this pathway, nine proteins were found to be differentially expressed: MHC class II (P20036, p = 0.02), G-protein αi family (P04899, p = 0.006), CalDAG-GEFI (Q7LDG7, p = 0.006), ARF6 (P62330, p = 0.013), actin (P68032, p = 0.011), actin cytoskeletal (P63261, p = 0.014), talin (Q9Y490, p = 0.015), ITGB2 (P05107, p = 0.046), and αLβ2 (P20701, p = 0.023; P05107, p = 0.046). MHC class II had a higher expression in UM-CLL (fold changes represented by a red thermometer). However, the other eight differentially expressed proteins had a lower expression in UM-CLL (fold changes represented by blue thermometers) compared with M-CLL. This suggests that migration into the tissue microenvironments via the αLβ2 integrin pathway may be dysfunctional in UM-CLL.
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.

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