Comparative analysis of normal versus CLL B-lymphocytes reveals patient-specific variability in signaling mechanisms controlling LFA-1 activation by chemokines

Cancer Research
Alessio MontresorCarlo Laudanna

Abstract

Activation of lymphocyte function-associated antigen-1 (LFA-1) by chemokines is fine-tuned by inside-out signaling mechanisms responsible for integrin-mediated adhesion modulation. In the present study, we investigated the possibility of qualitative variability of signaling mechanisms controlling LFA-1 activation in chronic lymphocytic leukemia (CLL) cells. We pursued a multiplexed comparative analysis of the role of the recently described chemokine-triggered rho-signaling module in human normal versus CLL B-lymphocytes. We found that the rho-module of LFA-1 affinity triggering is functionally conserved in normal B-lymphocytes. In contrast, in malignant B-lymphocytes isolated from patients with B-CLL, the role of the rho-module was not maintained, showing remarkable differences and variability. Specifically, RhoA and phospholipase D1 were crucially involved in LFA-1 affinity triggering by CXCL12 in all analyzed patients. In contrast, Rac1 and CDC42 involvement displayed a consistent patient-by-patient variability, with a group of patients showing LFA-1 affinity modulation totally independent of Rac1 and CDC42 signaling activity. Finally, phosphatidylinositol-4-phosphate 5-kinase isoform 1gamma (PIP5KC) was found without any reg...Continue Reading

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Citations

Dec 20, 2011·Nature Immunology·Gabriela Constantin, Carlo Laudanna
Dec 26, 2013·The Journal of Cell Biology·Alessio MontresorCarlo Laudanna
Jul 9, 2013·Seminars in Cancer Biology·Federico Caligaris-CappioCristina Scielzo
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Mar 30, 2021·Frontiers in Immunology·Michael J Shannon, Emily M Mace

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