title: Rewiring of sIgM-Mediated Intracellular Signaling through the CD180 Toll-like Receptor.
abstract: Chronic lymphocytic leukemia (CLL) development and progression are thought to be driven by unknown antigens/autoantigens through the B cell receptor (BCR) and environmental signals for survival and expansion including toll-like receptor (TLR) ligands. CD180/RP105, a membrane-associated orphan receptor of the TLR family, induces normal B cell activation and proliferation and is expressed by approximately 60% of CLL samples. Half of these respond to ligation with anti-CD180 antibody by increased activation/phosphorylation of protein kinases associated with BCR signaling. Hence CLL cells expressing both CD180 and the BCR could receive signals via both receptors. Here we investigated cross-talk between BCR and CD180-mediated signaling on CLL cell survival and apoptosis. Our data indicate that ligation of CD180 on responsive CLL cells leads to activation of either prosurvival Bruton tyrosine kinase (BTK)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT-mediated, or proapoptotic p38 mitogen-activated protein kinase (p38MAPK)-mediated signaling pathways, while selective immunoglobulin M (sIgM) ligation predominantly engages the BTK/PI3K/AKT pathway. Furthermore, pretreatment of CLL cells with anti-CD180 redirects IgM-mediated signaling from the prosurvival BTK/PI3K/AKT toward the proapoptotic p38MAPK pathway. Thus preengaging CD180 could prevent further prosurvival signaling mediated via the BCR and, instead, induce CLL cell apoptosis, opening the door to therapeutic profiling and new strategies for the treatment of a substantial cohort of CLL patients.
authors.affiliation: Faculty of Science and Technology, University of Westminster, London, United Kingdom.
authors.forename: Nino
authors.initials: N
authors.lastname: Porakishvili
authors.affiliation: Faculty of Science and Technology, University of Westminster, London, United Kingdom.
authors.forename: Ketki
authors.initials: K
authors.lastname: Vispute
authors.affiliation: University of Southampton, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Steele
authors.affiliation: Faculty of Science and Technology, University of Westminster, London, United Kingdom.
authors.forename: Nadeeka
authors.initials: N
authors.lastname: Rajakaruna
authors.affiliation: Faculty of Science and Technology, University of Westminster, London, United Kingdom.|Javakhishvili Tbilisi State University, Georgia.
authors.forename: Nina
authors.initials: N
authors.lastname: Kulikova
authors.affiliation: Javakhishvili Tbilisi State University, Georgia.
authors.forename: Tamar
authors.initials: T
authors.lastname: Tsertsvadze
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Amit
authors.initials: A
authors.lastname: Nathwani
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Rajendra N
authors.initials: RN
authors.lastname: Damle
authors.affiliation: University of Washington, Seattle, Washington, United States of America.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Clark
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: Faculty of Science and Technology, University of Westminster, London, United Kingdom.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lydyard