The VLA-4 integrin is constitutively active in circulating chronic lymphocytic leukemia cells via BCR autonomous signaling: a novel anchor-independent mechanism exploiting soluble blood-borne ligands

  1. Tissino, Erika ORCID logo
  2. Gaglio, Annalisa
  3. Nicolò, Antonella
  4. Pozzo, Federico ORCID logo
  5. Bittolo, Tamara
  6. rossi, francesca maria ORCID logo
  7. Bomben, Riccardo ORCID logo
  8. Nanni, Paola
  9. Cattarossi, Ilaria
  10. Zaina, Eva
  11. Zimbo, Anna Maria
  12. Ianna, Giulia
  13. Capasso, Guido
  14. Forestieri, Gabriela
  15. Moia, Riccardo ORCID logo
  16. Datta, Moumita
  17. Härzschel, Andrea
  18. Olivieri, Jacopo
  19. D'Arena, Giovanni ORCID logo
  20. Laurenti, Luca
  21. Zaja, Francesco
  22. Chiarenza, Annalisa
  23. PALUMBO, Giuseppe Alberto Maria ORCID logo
  24. Martino, Enrica Antonia
  25. Gentile, Massimo ORCID logo
  26. Rossi, Davide
  27. Gaidano, Gianluca
  28. Del Poeta, Giovanni
  29. Laureana, Roberta
  30. Del Principe, Maria Ilaria
  31. Maity, Palash C.
  32. Jumaa, Hassan ORCID logo
  33. Hartmann, Tanja Nicole ORCID logo
  34. Zucchetto, Antonella
  35. gattei, valter ORCID logo

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1000 Titel
  • The VLA-4 integrin is constitutively active in circulating chronic lymphocytic leukemia cells via BCR autonomous signaling: a novel anchor-independent mechanism exploiting soluble blood-borne ligands
1000 Autor/in
  1. Tissino, Erika |
  2. Gaglio, Annalisa |
  3. Nicolò, Antonella |
  4. Pozzo, Federico |
  5. Bittolo, Tamara |
  6. rossi, francesca maria |
  7. Bomben, Riccardo |
  8. Nanni, Paola |
  9. Cattarossi, Ilaria |
  10. Zaina, Eva |
  11. Zimbo, Anna Maria |
  12. Ianna, Giulia |
  13. Capasso, Guido |
  14. Forestieri, Gabriela |
  15. Moia, Riccardo |
  16. Datta, Moumita |
  17. Härzschel, Andrea |
  18. Olivieri, Jacopo |
  19. D'Arena, Giovanni |
  20. Laurenti, Luca |
  21. Zaja, Francesco |
  22. Chiarenza, Annalisa |
  23. PALUMBO, Giuseppe Alberto Maria |
  24. Martino, Enrica Antonia |
  25. Gentile, Massimo |
  26. Rossi, Davide |
  27. Gaidano, Gianluca |
  28. Del Poeta, Giovanni |
  29. Laureana, Roberta |
  30. Del Principe, Maria Ilaria |
  31. Maity, Palash C. |
  32. Jumaa, Hassan |
  33. Hartmann, Tanja Nicole |
  34. Zucchetto, Antonella |
  35. gattei, valter |
1000 Verlag Nature Publishing Group UK
1000 Erscheinungsjahr 2024
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2024-08-14
1000 Erschienen in
1000 Quellenangabe
  • 38(10):2127-2140
1000 Copyrightjahr
  • 2024
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1038/s41375-024-02376-7 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11436378/ |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • In chronic lymphocytic leukemia (CLL), survival of neoplastic cells depends on microenvironmental signals at lymphoid sites where the crosstalk between the integrin VLA-4 (CD49d/CD29), expressed in ~40% of CLL, and the B-cell receptor (BCR) occurs. Here, BCR engagement inside-out activates VLA-4, thus enhancing VLA-4-mediated adhesion of CLL cells, which in turn obtain pro-survival signals from the surrounding microenvironment. We report that the BCR is also able to effectively inside-out activate the VLA-4 integrin in circulating CD49d-expressing CLL cells through an autonomous antigen-independent BCR signaling. As a consequence, circulating CLL cells exhibiting activated VLA-4 express markers of BCR pathway activation (phospho-BTK and phospho-PLC-γ2) along with higher levels of phospho-ERK and phospho-AKT indicating parallel activation of downstream pathways. Moreover, circulating CLL cells expressing activated VLA-4 bind soluble blood-borne VCAM-1 leading to increased VLA-4-dependent actin polymerization/re-organization and ERK phosphorylation. Finally, evidence is provided that ibrutinib treatment, by affecting autonomous BCR signaling, impairs the constitutive VLA-4 activation eventually decreasing soluble VCAM-1 binding and reducing downstream ERK phosphorylation by circulating CLL cells. This study describes a novel anchor-independent mechanism occurring in circulating CLL cells involving the BCR and the VLA-4 integrin, which help to unravel the peculiar biological and clinical features of CD49d+ CLL.
1000 Sacherschließung
lokal /96
lokal Adenine/pharmacology [MeSH]
lokal Vascular Cell Adhesion Molecule-1/metabolism [MeSH]
lokal Leukemia, Lymphocytic, Chronic, B-Cell/metabolism [MeSH]
lokal Pyrazoles/therapeutic use [MeSH]
lokal /13
lokal /631/67/1990/283/1895
lokal Leukemia, Lymphocytic, Chronic, B-Cell/pathology [MeSH]
lokal Ligands [MeSH]
lokal /38/109
lokal Receptors, Antigen, B-Cell/metabolism [MeSH]
lokal /13/31
lokal Pyrimidines/pharmacology [MeSH]
lokal Adenine/analogs
lokal Neoplastic Cells, Circulating/pathology [MeSH]
lokal /82/80
lokal Cell Adhesion [MeSH]
lokal Humans [MeSH]
lokal Pyrazoles/pharmacology [MeSH]
lokal /13/106
lokal Neoplastic Cells, Circulating/metabolism [MeSH]
lokal Integrin alpha4beta1/metabolism [MeSH]
lokal Article
lokal Signal Transduction [MeSH]
lokal /631/80/86
lokal /14
lokal article
lokal Piperidines/pharmacology [MeSH]
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0001-6093-1649|https://frl.publisso.de/adhoc/uri/R2FnbGlvLCBBbm5hbGlzYQ==|https://frl.publisso.de/adhoc/uri/Tmljb2zDsiwgQW50b25lbGxh|https://orcid.org/0000-0002-2986-7658|https://frl.publisso.de/adhoc/uri/Qml0dG9sbywgVGFtYXJh|https://orcid.org/0000-0001-8438-1661|https://orcid.org/0000-0002-8746-9404|https://frl.publisso.de/adhoc/uri/TmFubmksIFBhb2xh|https://frl.publisso.de/adhoc/uri/Q2F0dGFyb3NzaSwgSWxhcmlh|https://frl.publisso.de/adhoc/uri/WmFpbmEsIEV2YQ==|https://frl.publisso.de/adhoc/uri/WmltYm8sIEFubmEgTWFyaWE=|https://frl.publisso.de/adhoc/uri/SWFubmEsIEdpdWxpYQ==|https://frl.publisso.de/adhoc/uri/Q2FwYXNzbywgR3VpZG8=|https://frl.publisso.de/adhoc/uri/Rm9yZXN0aWVyaSwgR2FicmllbGE=|https://orcid.org/0000-0001-7393-1138|https://frl.publisso.de/adhoc/uri/RGF0dGEsIE1vdW1pdGE=|https://frl.publisso.de/adhoc/uri/SMOkcnpzY2hlbCwgQW5kcmVh|https://frl.publisso.de/adhoc/uri/T2xpdmllcmksIEphY29wbw==|https://orcid.org/0000-0002-3807-7287|https://frl.publisso.de/adhoc/uri/TGF1cmVudGksIEx1Y2E=|https://frl.publisso.de/adhoc/uri/WmFqYSwgRnJhbmNlc2Nv|https://frl.publisso.de/adhoc/uri/Q2hpYXJlbnphLCBBbm5hbGlzYQ==|https://orcid.org/0000-0003-1859-6319|https://frl.publisso.de/adhoc/uri/TWFydGlubywgRW5yaWNhIEFudG9uaWE=|https://orcid.org/0000-0002-5256-0726|https://frl.publisso.de/adhoc/uri/Um9zc2ksIERhdmlkZQ==|https://frl.publisso.de/adhoc/uri/R2FpZGFubywgR2lhbmx1Y2E=|https://frl.publisso.de/adhoc/uri/RGVsIFBvZXRhLCBHaW92YW5uaQ==|https://frl.publisso.de/adhoc/uri/TGF1cmVhbmEsIFJvYmVydGE=|https://frl.publisso.de/adhoc/uri/RGVsIFByaW5jaXBlLCBNYXJpYSBJbGFyaWE=|https://frl.publisso.de/adhoc/uri/TWFpdHksIFBhbGFzaCBDLg==|https://orcid.org/0000-0003-3383-141X|https://orcid.org/0000-0002-0377-7179|https://frl.publisso.de/adhoc/uri/WnVjY2hldHRvLCBBbnRvbmVsbGE=|https://orcid.org/0000-0001-5933-9680
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1000 Erstellt am 2025-02-06T19:35:00.009+0100
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