Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis

Sic, Heiko; Kraus, Herbert; Madl, Josef; Flittner, Karl Andreas; Münchow, Audrey Lilly Von; Pieper, Kathrin; Rizzi, Marta; Kienzler, Anne‐Kathrin; Ayata, Cemil Korcan; Rauer, Sebastian; Kleuser, Burkhard; Salzer, Ulrich; Burger, Meike; Zirlik, Katja; Lougaris, Vassilios; Plebani, Alessandro; Römer, Winfried; Loeffler, Christoph; Scaramuzza, Samantha; Villa, Anna; Noguchi, Emiko; Grimbacher, Bodo; Eibel, Hermann

doi:10.1016/j.jaci.2014.01.037

Cited by 73 publications

(67 citation statements)

References 47 publications

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“…In line with this, we speculate that CLL cells that enter lymphoid tissues but do not actively interact with the supportive microenvironment will not reduce their S1PR1 expression, favoring a more rapid return to the circulation. In accordance with a recent report (37), our results with healthy B cells suggest that the modulation of S1PR1 expression that is induced by B cell activation may also regulate their exit from lymphoid organs.…”

Section: Discussionsupporting

confidence: 93%

The Expression of Sphingosine-1 Phosphate Receptor-1 in Chronic Lymphocytic Leukemia Cells Is Impaired by Tumor Microenvironmental Signals and Enhanced by Piceatannol and R406

Borge

Lenicov

Nannini

et al. 2014

The Journal of Immunology

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Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of clonal B lymphocytes. Proliferation occurs in lymphoid tissues upon interaction of leukemic cells with a supportive microenvironment. Therefore, the mobilization of tissue-resident CLL cells into the circulation is a useful therapeutic strategy to minimize the reservoir of tumor cells within survival niches. Because the exit of normal lymphocytes from lymphoid tissues depends on the presence of sphingosine-1 phosphate (S1P) and the regulated expression of S1P receptor-1 (S1PR1), we investigated whether the expression and function of S1PR1 can be modulated by key microenvironment signals. We found that activation of CLL cells with CXCL12, fibroblast CD40L+, BCR cross-linking, or autologous nurse-like cells reduces their S1PR1 expression and the migratory response toward S1P. Moreover, we found that S1PR1 expression was reduced in the proliferative/activated subset of leukemic cells compared with the quiescent subset from the same patient. Similarly, bone marrow–resident CLL cells expressing high levels of the activation marker CD38 showed a lower expression of S1PR1 compared with CD38low counterparts. Finally, given that treatment with BCR-associated kinase inhibitors induces a transient redistribution of leukemic cells from lymphoid tissues to circulation, we studied the effect of the Syk inhibitors piceatannol and R406 on S1PR1 expression and function. We found that they enhance S1PR1 expression in CLL cells and their migratory response toward S1P. Based on our results, we suggest that the regulated expression of S1PR1 might modulate the egress of the leukemic clone from lymphoid tissues.

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Section: Discussionsupporting

confidence: 93%

The Expression of Sphingosine-1 Phosphate Receptor-1 in Chronic Lymphocytic Leukemia Cells Is Impaired by Tumor Microenvironmental Signals and Enhanced by Piceatannol and R406

Borge

Lenicov

Nannini

et al. 2014

The Journal of Immunology

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“…‘Ocrelizumab’11 or ‘rituximab’12 depletes CD20 + B cells. ‘Fingolimod’13 acts as a functional antagonist of the sphingosine-1-phosphate receptor, precludes migration of CCR7 + central memory T cells into the CNS and also exerts effects on B-lymphocyte migration and function 14 15. For relapsing–remitting MS (RRMS), they target defined pathways of the immune system, rapidly decrease CNS inflammation and reduce relapse rates via direct targeting of single molecules in the immune system.…”

Section: Neurodegeneration In Msmentioning

confidence: 99%

Neurodegeneration in multiple sclerosis and neuromyelitis optica

Kawachi

Lassmann

2016

J Neurol Neurosurg Psychiatry

229

161

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“…The analysis of Was -/-mice clearly points out defects in B cells, suggesting impairment in the removal of autoreactive B cells (9)(10)(11). B cells from WAS patients show defects in migration and adhesion because of defective actin polymerization and poor migration toward S1P, as well as SDF1α (12)(13)(14). B cell counts usually decrease with age in addition to a skewed distribution of serum immunoglobulins and impaired response to T cell-independent antigens (15,16).…”

Section: Introductionmentioning

confidence: 99%

Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients

Pala¹,

Morbach²,

Castiello³

et al. 2015

Journal of Clinical Investigation

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Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis

Cited by 73 publications

References 47 publications

The Expression of Sphingosine-1 Phosphate Receptor-1 in Chronic Lymphocytic Leukemia Cells Is Impaired by Tumor Microenvironmental Signals and Enhanced by Piceatannol and R406

The Expression of Sphingosine-1 Phosphate Receptor-1 in Chronic Lymphocytic Leukemia Cells Is Impaired by Tumor Microenvironmental Signals and Enhanced by Piceatannol and R406

Neurodegeneration in multiple sclerosis and neuromyelitis optica

Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients

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