title: 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) LTD(4) 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.
authors.affiliation: Department of Hematology, Oncology, Rheumatology, Clinical Immunology and Pulmology, University Hospital Tübingen, Tübingen, Germany. adriana.drost@med.uni-tuebingen.de
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Drost
authors.forename: Gabriele
authors.initials: G
authors.lastname: Seitz
authors.forename: Andreas
authors.initials: A
authors.lastname: Boehmler
authors.forename: Mirjam
authors.initials: M
authors.lastname: Funk
authors.forename: Karoline Pia
authors.initials: KP
authors.lastname: Norz
authors.forename: Anne
authors.initials: A
authors.lastname: Zipfel
authors.forename: Xingkui
authors.initials: X
authors.lastname: Xue
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.forename: Robert
authors.initials: R
authors.lastname: Möhle
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018925:Chemokines / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D003545:Cysteine / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology*; D015289:Leukotrienes / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000098:Acetophenones; D000199:Actins; D018925:Chemokines; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011422:Propionates; D011804:Quinolines; D018077:Receptors, Leukotriene; D013777:Tetrazoles; C112381:cysteinyl-leukotriene; C059141:verlukast; D017998:Leukotriene D4; C044660:LY 171883; D020928:Mitogen-Activated Protein Kinases; D003545:Cysteine; C083169:leukotriene D4 receptor; D002118:Calcium