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p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB

The microenvironment of lymphoid organs is central to the pathogenesis of chronic lymphocytic leukemia (CLL). Within it, tumor cells find a favourable niche to escape immunosurveillance and acquire pro-survival signals. We have previously reported that a CLL-associated defect in the expression of th...

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Autores principales: Tatangelo, Vanessa, Boncompagni, Gioia, Capitani, Nagaja, Lopresti, Ludovica, Manganaro, Noemi, Frezzato, Federica, Visentin, Andrea, Trentin, Livio, Baldari, Cosima T., Patrussi, Laura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278989/
https://www.ncbi.nlm.nih.gov/pubmed/35847884
http://dx.doi.org/10.3389/fonc.2022.877495
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author Tatangelo, Vanessa
Boncompagni, Gioia
Capitani, Nagaja
Lopresti, Ludovica
Manganaro, Noemi
Frezzato, Federica
Visentin, Andrea
Trentin, Livio
Baldari, Cosima T.
Patrussi, Laura
author_facet Tatangelo, Vanessa
Boncompagni, Gioia
Capitani, Nagaja
Lopresti, Ludovica
Manganaro, Noemi
Frezzato, Federica
Visentin, Andrea
Trentin, Livio
Baldari, Cosima T.
Patrussi, Laura
author_sort Tatangelo, Vanessa
collection PubMed
description The microenvironment of lymphoid organs is central to the pathogenesis of chronic lymphocytic leukemia (CLL). Within it, tumor cells find a favourable niche to escape immunosurveillance and acquire pro-survival signals. We have previously reported that a CLL-associated defect in the expression of the pro-apoptotic and pro-oxidant adaptor p66Shc leads to enhanced homing to and accumulation of leukemic cells in the lymphoid microenvironment. The p66Shc deficiency-related impairment in intracellular reactive oxygen species (ROS) production in CLL cells is causally associated to the enhanced expression of the chemokine receptors CCR2, CXCR3 and CCR7, that promote leukemic cell homing to both lymphoid and non-lymphoid organs, suggesting the implication of a ROS-modulated transcription factor(s). Here we show that the activity of the ROS-responsive p65 subunit of the transcription factor NF-κB was hampered in the CLL-derived cell line MEC-1 expressing a NF-κB-luciferase reporter following treatment with H(2)O(2). Similar results were obtained when intracellular ROS were generated by expression of p66Shc, but not of a ROS-defective mutant, in MEC-1 cells. NF-κB activation was associated with increased expression of the chemokine receptors CCR2, CXCR3 and CCR7. Reconstitution of p66Shc in CLL cells normalized intracellular ROS and hampered NF-κB activation, which led to a decrease in the expression of these homing receptors. Our data provide direct evidence that the p66Shc-deficiency-related ROS depletion in CLL cells concurs to NF-κB hyperactivation and homing receptor overexpression, providing a mechanistic basis for the enhanced ability of these cells to accumulate in the pro-survival lymphoid niche.
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spelling pubmed-92789892022-07-14 p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB Tatangelo, Vanessa Boncompagni, Gioia Capitani, Nagaja Lopresti, Ludovica Manganaro, Noemi Frezzato, Federica Visentin, Andrea Trentin, Livio Baldari, Cosima T. Patrussi, Laura Front Oncol Oncology The microenvironment of lymphoid organs is central to the pathogenesis of chronic lymphocytic leukemia (CLL). Within it, tumor cells find a favourable niche to escape immunosurveillance and acquire pro-survival signals. We have previously reported that a CLL-associated defect in the expression of the pro-apoptotic and pro-oxidant adaptor p66Shc leads to enhanced homing to and accumulation of leukemic cells in the lymphoid microenvironment. The p66Shc deficiency-related impairment in intracellular reactive oxygen species (ROS) production in CLL cells is causally associated to the enhanced expression of the chemokine receptors CCR2, CXCR3 and CCR7, that promote leukemic cell homing to both lymphoid and non-lymphoid organs, suggesting the implication of a ROS-modulated transcription factor(s). Here we show that the activity of the ROS-responsive p65 subunit of the transcription factor NF-κB was hampered in the CLL-derived cell line MEC-1 expressing a NF-κB-luciferase reporter following treatment with H(2)O(2). Similar results were obtained when intracellular ROS were generated by expression of p66Shc, but not of a ROS-defective mutant, in MEC-1 cells. NF-κB activation was associated with increased expression of the chemokine receptors CCR2, CXCR3 and CCR7. Reconstitution of p66Shc in CLL cells normalized intracellular ROS and hampered NF-κB activation, which led to a decrease in the expression of these homing receptors. Our data provide direct evidence that the p66Shc-deficiency-related ROS depletion in CLL cells concurs to NF-κB hyperactivation and homing receptor overexpression, providing a mechanistic basis for the enhanced ability of these cells to accumulate in the pro-survival lymphoid niche. Frontiers Media S.A. 2022-06-29 /pmc/articles/PMC9278989/ /pubmed/35847884 http://dx.doi.org/10.3389/fonc.2022.877495 Text en Copyright © 2022 Tatangelo, Boncompagni, Capitani, Lopresti, Manganaro, Frezzato, Visentin, Trentin, Baldari and Patrussi https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Tatangelo, Vanessa
Boncompagni, Gioia
Capitani, Nagaja
Lopresti, Ludovica
Manganaro, Noemi
Frezzato, Federica
Visentin, Andrea
Trentin, Livio
Baldari, Cosima T.
Patrussi, Laura
p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB
title p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB
title_full p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB
title_fullStr p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB
title_full_unstemmed p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB
title_short p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB
title_sort p66shc deficiency in chronic lymphocytic leukemia promotes chemokine receptor expression through the ros-dependent inhibition of nf-κb
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278989/
https://www.ncbi.nlm.nih.gov/pubmed/35847884
http://dx.doi.org/10.3389/fonc.2022.877495
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