Abnormalities in chemokine receptor recycling in chronic lymphocytic leukemia

Patrussi, Laura; Capitani, Nagaja; Baldari, Cosima T.

doi:10.1007/s00018-019-03058-9

Cited by 8 publications

(9 citation statements)

References 120 publications

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“…The chemotactic ability of cells within spleen slices either immediately after cutting or cultured for 48 h at 37 • C was analyzed by Transwell assays. Intact slices were placed on the upper wells of Boyden chambers and cells were allowed to migrate to the lower wells toward the chemokines CXCL12 or MIP-3β, which bind the respective lymphocyte-specific receptors CXCR4 and CCR7 (17). Migrated T and B cells were then stained with anti-mouse CD3 PE and anti-mouse CD19 FITC antibodies and quantified by flow cytometry.…”

Section: Spleen Slices Cultured For 48 H In Vitro Are Responsive To Ementioning

confidence: 99%

Optimization of Organotypic Cultures of Mouse Spleen for Staining and Functional Assays

et al. 2020

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By preserving cell viability and three-dimensional localization, organotypic culture stands out among the newest frontiers of cell culture. It has been successfully employed for the study of diseases among which neoplasias, where tumoral cells take advantage of the surrounding stroma to promote their own proliferation and survival. Organotypic culture acquires major importance in the context of the immune system, whose cells cross-talk in a complex and dynamic fashion to elicit productive responses. However, organotypic culture has been as yet poorly developed for and applied to primary and secondary lymphoid organs. Here we describe in detail the development of a protocol suitable for the efficient cutting of mouse spleen, which overcomes technical difficulties related to the peculiar organ texture, and for optimized organotypic culture of spleen slices. Moreover, we used microscopy, immunofluorescence, flow cytometry, and qRT-PCR to demonstrate that the majority of cells residing in spleen slices remain alive and maintain their original location in the organ architecture for several days after cutting. The development of this protocol represents a significant technical improvement in the study of the lymphoid microenvironment in both physiological and pathological conditions involving the immune system.

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Section: Spleen Slices Cultured For 48 H In Vitro Are Responsive To Ementioning

confidence: 99%

Optimization of Organotypic Cultures of Mouse Spleen for Staining and Functional Assays

et al. 2020

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“…CLL B cells are characterized by trafficking abnormalities that strongly contribute to their prolonged survival. Their enhanced ability to home to peripheral lymphoid organs and bone marrow, together with their failure to efficiency egress therefrom, leads to a prolonged residency into the lymphoid stromal niche, where they acquire proliferation and survival cues [10,12]. The altered traffic of CLL B cells can be ascribed, at least in part, to abnormally high levels of chemokine receptors at their surface [12,52,[81][82][83][84][85].…”

Section: P66shc Expression Impinges On the Expression Of Trafficking Receptorsmentioning

confidence: 99%

“…Their enhanced ability to home to peripheral lymphoid organs and bone marrow, together with their failure to efficiency egress therefrom, leads to a prolonged residency into the lymphoid stromal niche, where they acquire proliferation and survival cues [10,12]. The altered traffic of CLL B cells can be ascribed, at least in part, to abnormally high levels of chemokine receptors at their surface [12,52,[81][82][83][84][85]. CLL B cells overexpress chemokine receptors which guide lymphocyte homing to both nodal and extranodal sites, including CXCR4, CCR7, CXCR5, CXCR3 and CCR2 [52,[81][82][83][84][86][87][88][89][90][91][92][93].…”

Section: P66shc Expression Impinges On the Expression Of Trafficking Receptorsmentioning

confidence: 99%

“…On the other hand, p66Shc deficiency in CLL B cells from patients with unfavorable prognosis directly correlates to their abnormally low levels of the surface receptor S1PR1 [84] whose ligand, the sphingolipid S1P (sphingosine 1-phosphate), promotes lymphocyte egress from lymphoid organs [94]. The enhanced expression of homing receptors, and the defective S1PR1 expression harbored by CLL B cells from these patients, both contribute to the accumulation of CLL cells in the pro-survival niche of lymphoid organs [12]. Importantly, forced p66Shc expression in CLL cells normalizes the expression of these homing and egress receptors and restores chemotaxis towards the respective ligands [52,84], implicating residual p66Shc expression levels as a checkpoint of infiltrating vs non-infiltrating leukemia.…”

Section: P66shc Expression Impinges On the Expression Of Trafficking Receptorsmentioning

confidence: 99%

“…In addition to these intrinsic factors, several reports have recently highlighted the complex interplay between CLL B cells and the lymphoid microenvironment as a source of extrinsically-derived factors which make leukemic cells more prone to circumvent apoptosis [1,10]. This is further exacerbated by the abnormally high expression of chemokine receptors on the surface of CLL B cells, which promotes their trafficking and favors their retention in the pro-survival stromal niche [11,12].…”

Section: Introductionmentioning

confidence: 99%

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P66Shc: A Pleiotropic Regulator of B Cell Trafficking and a Gatekeeper in Chronic Lymphocytic Leukemia

Patrussi

Capitani

Baldari

2020

Cancers

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Neoplastic B cells from chronic lymphocytic leukemia patients (CLL) have a profound deficiency in the expression of p66Shc, an adaptor protein with pro-apoptotic and pro-oxidant activities. This defect results in leukemic B cell resistance to apoptosis and additionally impinges on the balance between chemokine receptors that control B cell homing to secondary lymphoid organs and the sphingosine phosphate receptor S1PR1 that controls their egress therefrom, thereby favoring leukemic B cell accumulation in the pro-survival lymphoid niche. Ablation of the gene encoding p66Shc in the Eµ-TCL1 mouse model of human CLL enhances leukemogenesis and promotes leukemic cell invasiveness in both nodal and extranodal organs, providing in vivo evidence of the pathogenic role of the p66Shc defect in CLL pathogenesis. Here we present an overview of the functions of p66Shc in B lymphocytes, with a specific focus on the multiple mechanisms exploited by p66Shc to control B cell trafficking and the abnormalities in this process caused by p66Shc deficiency in CLL.

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A novel class of oxazepine-based anti-cancer agents induces cell death in primary human CLL cells and efficiently reduces tumor growth in Eμ-TCL1 mice through the JNK/STAT4/p66Shc axis

Vanni

Lopresti

Zurli

et al. 2021

Pharmacological Research

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Abnormalities in chemokine receptor recycling in chronic lymphocytic leukemia

Cited by 8 publications

References 120 publications

Optimization of Organotypic Cultures of Mouse Spleen for Staining and Functional Assays

Optimization of Organotypic Cultures of Mouse Spleen for Staining and Functional Assays

P66Shc: A Pleiotropic Regulator of B Cell Trafficking and a Gatekeeper in Chronic Lymphocytic Leukemia

A novel class of oxazepine-based anti-cancer agents induces cell death in primary human CLL cells and efficiently reduces tumor growth in Eμ-TCL1 mice through the JNK/STAT4/p66Shc axis

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