The G protein-coupled receptor CysLT1 mediates chemokine-like effects and prolongs survival in chronic lymphocytic leukemia

Abstract The G protein-coupled receptor (GPCR) CXCR4 is involved in bone marrow tropism and survival of chronic lymphocytic leukemia (CLL) cells. The function of the GPCRs cysteinyl leukotriene receptor 1 (CysLT1) and CysLT2 remains elusive. Here we demonstrate that in CLL and normal B lymphocytes, CysLT1 mRNA is consistently expressed, in contrast to low CysLT2 levels. Similar to the CXCR4 ligand CXCL12, the cysteinyl leukotriene (cysLT) LTD4 induces calcium fluxes, actin polymerization, and chemotaxis. These effects are blocked by specific CysLT1 antagonists. Their inhibition by pertussis toxin suggests Giα/o protein involvement. Furthermore, CysLT1 mediates MAP-kinase phosphorylation, which implicates contribution of cysLT to survival. Indeed, CysLT1 antagonists induce apoptosis and reduce viability independent of Gαi/o protein signaling. Considering the production of cysLTs in the bone marrow, our data suggest that CysLT1 induces chemokine-like effects, supports accumulation and survival of CLL cells in the bone marrow and thus represents a potential treatment target.

[1]  T. Goodson,et al.  LY171883, 1-less than 2-hydroxy-3-propyl-4-less than 4-(1H-tetrazol-5-yl) butoxy greater than phenyl greater than ethanone, an orally active leukotriene D4 antagonist. , 1985, The Journal of pharmacology and experimental therapeutics.

[2]  P. Cannon,et al.  Endothelial cell leukotriene C4 synthesis results from intercellular transfer of leukotriene A4 synthesized by polymorphonuclear leukocytes. , 1986, The Journal of biological chemistry.

[3]  J. Ceuppens,et al.  Flow cytometric measurement of cytoplasmic free calcium in human peripheral blood T lymphocytes with fluo-3, a new fluorescent calcium indicator. , 1990, Journal of immunological methods.

[4]  Anti-asthmatic Drugs , 1990 .

[5]  Formation and effects of leukotrienes and lipoxins in human bone marrow. , 1993, Journal of lipid mediators.

[6]  D. Nicholson,et al.  Identification and target-size analysis of the leukotriene D4 receptor in the human THP-1 cell line. , 1993, Biochimica et biophysica acta.

[7]  G. Kruh,et al.  Structure and in vitro substrate specificity of the murine multidrug resistance-associated protein. , 1996, Biochemistry.

[8]  C. Denzlinger,et al.  Biology and pathophysiology of leukotrienes. , 1996, Critical reviews in oncology/hematology.

[9]  S. Rafii,et al.  The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. , 1998, Blood.

[10]  J. Lindgren,et al.  Novel enzymatic abnormalities in AML and CML in blast crisis: elevated leucocyte leukotriene C4 synthase activity paralleled by deficient leukotriene biosynthesis from endogenous substrate , 1998, British journal of haematology.

[11]  W. Busse.  Leukotrienes and inflammation. , 1998, American journal of respiratory and critical care medicine.

[12]  Jilly F. Evans,et al.  Characterization of the human cysteinyl leukotriene CysLT1 receptor , 1999, Nature.

[13]  J. Chambers,et al.  Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. , 1999, Molecular pharmacology.

[14]  R. Alon,et al.  Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. , 1999, Science.

[15]  Thomas J. Kipps,et al.  Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. , 1999 .

[16]  L. Kanz,et al.  Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1) , 1999, Leukemia.

[17]  T. Springer,et al.  The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. , 1999, Immunity.

[18]  S. Rafii,et al.  Regulation of Transendothelial Migration of Hematopoietic Progenitor Cells , 1999, Annals of the New York Academy of Sciences.

[19]  H. Claesson,et al.  Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs , 1999, Journal of internal medicine.

[20]  R. Paroni,et al.  Human CD34(+) cells express CXCR4 and its ligand stromal cell-derived factor-1. Implications for infection by T-cell tropic human immunodeficiency virus. , 1999, Blood.

[21]  M. Le Bousse-Kerdilès,et al.  Chemokine SDF-1 enhances circulating CD34(+) cell proliferation in synergy with cytokines: possible role in progenitor survival. , 2000, Blood.

[22]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[23]  Jilly F. Evans,et al.  Characterization of the Human Cysteinyl Leukotriene 2 Receptor* , 2000, The Journal of Biological Chemistry.

[24]  L. Kanz,et al.  Chemotaxis and transendothelial migration of CD34(+) hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1. , 2001, Blood.

[25]  J. Lehman,et al.  MAP kinase upregulation after hematopoietic differentiation: role of chemotaxis. , 2001, American journal of physiology. Cell physiology.

[26]  C Stratowa,et al.  CDNA microarray gene expression analysis of B‐cell chronic lymphocytic leukemia proposes potential new prognostic markers involved in lymphocyte trafficking , 2001, International journal of cancer.

[27]  C. Funk,et al.  Cysteinyl leukotriene receptors. , 2002, Biochemical pharmacology.

[28]  L. J. Woods,et al.  Intracrine Cysteinyl Leukotriene Receptor–mediated Signaling of Eosinophil Vesicular Transport–mediated Interleukin-4 Secretion , 2002, The Journal of experimental medicine.

[29]  W. Henderson,et al.  Lipid inflammatory mediators: leukotrienes, prostaglandins, platelet-activating factor. , 2002, Clinical allergy and immunology.

[30]  Andrea Califano,et al.  Identification of Hodgkin and Reed-Sternberg cell-specific genes by gene expression profiling. , 2003, The Journal of clinical investigation.

[31]  Potential role of cysteinyl leukotrienes in trafficking and survival of hematopoietic progenitor cells. , 2003, Advances in experimental medicine and biology.

[32]  A. Sjölander,et al.  Leukotriene D4-induced adhesion of Caco-2 cells is mediated by prostaglandin E2 and upregulation of α2β1-integrin , 2003 .

[33]  A. Sjölander,et al.  Leukotriene D4-induced adhesion of Caco-2 cells is mediated by prostaglandin E2 and upregulation of alpha2beta1-integrin. , 2003, Experimental cell research.

[34]  G. Landberg,et al.  Expression of the leukotriene D4 receptor CysLT1, COX-2, and other cell survival factors in colorectal adenocarcinomas. , 2003, Gastroenterology.

[35]  J. Palmblad,et al.  Dominant Expression of the CysLT2 Receptor Accounts for Calcium Signaling by Cysteinyl Leukotrienes in Human Umbilical Vein Endothelial Cells , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[36]  Y. Kanaoka,et al.  Cysteinyl Leukotrienes and Their Receptors: Cellular Distribution and Function in Immune and Inflammatory Responses1 , 2004, The Journal of Immunology.

[37]  A. Ferrante,et al.  Characterization of the MEK5-ERK5 Module in Human Neutrophils and Its Relationship to ERK1/ERK2 in the Chemotactic Response* , 2004, Journal of Biological Chemistry.

[38]  O. Kollet,et al.  How do stem cells find their way home? , 2005, Blood.

[39]  Xunbin Wei,et al.  In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment , 2005, Nature.

[40]  D. Mungan,et al.  The effect of montelukast on eosinophil apoptosis: induced sputum findings of patients with mild persistent asthma. , 2005, Allergologia et immunopathologia.

[41]  N. Chiorazzi,et al.  mechanisms of disease Chronic Lymphocytic Leukemia , 2010 .

[42]  K. Riesbeck,et al.  A novel localization of the G-protein-coupled CysLT1 receptor in the nucleus of colorectal adenocarcinoma cells. , 2005, Cancer research.

[43]  E. Klein,et al.  Leukotriene B4 plays a pivotal role in CD40-dependent activation of chronic B lymphocytic leukemia cells. , 2004, Blood.

[44]  Hirokazu Tamamura,et al.  Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. , 2005, Blood.

[45]  J. Stankova,et al.  Leukotriene D4 enhances immunoglobulin production in CD40-activated human B lymphocytes. , 2006, The Journal of allergy and clinical immunology.

[46]  G. Seitz,et al.  Differential Effects of G Protein–Coupled Receptors on Hematopoietic Progenitor Cell Growth Depend on their Signaling Capacities , 2007, Annals of the New York Academy of Sciences.

[47]  Y. Kawahito,et al.  Overexpression of cysteinyl LT1 receptor in prostate cancer and CysLT1R antagonist inhibits prostate cancer cell growth through apoptosis. , 2007, Oncology reports.

[48]  J. Burger,et al.  The CXCR4 chemokine receptor in acute and chronic leukaemia: a marrow homing receptor and potential therapeutic target , 2007, British journal of haematology.

[49]  A. Sjölander,et al.  The Role of Leukotriene Receptor Signaling in Inflammation and Cancer , 2007, TheScientificWorldJournal.

[50]  A. Drost,et al.  The CysLT1 Ligand Leukotriene D4 Supports α4β1- and α5β1-Mediated Adhesion and Proliferation of CD34+ Hematopoietic Progenitor Cells1 , 2009, The Journal of Immunology.

[51]  Tomoaki Tanaka,et al.  Relationship between cysteinyl-leukotriene-1 receptor and human transitional cell carcinoma in bladder. , 2009, Urology.

[52]  A. Ray,et al.  Cysteinyl Leukotrienes and Their Receptors: Molecular and Functional Characteristics , 2010, Pharmacology.

[53]  S. Malek,et al.  Chronic Lymphocytic Leukemia , 2019, Methods in Molecular Biology.

[54]  F. Segal,et al.  A CHARACTERIZATION OF FIBRANT SEGAL CATEGORIES , 2006, math/0603400.