title: Lymphocyte cytosolic protein 1 is a chronic lymphocytic leukemia membrane-associated antigen critical to niche homing.
abstract: Membrane antigens are critical to the pathogenesis of chronic lymphocytic leukemia (CLL) as they facilitate microenvironment homing, proliferation, and survival. Targeting the CLL membrane and associated signaling patterns is a current focus of therapeutic development. Many tumor membrane targets are simultaneously targeted by humoral immunity, thus forming recognizable immunoglobulin responses. We sought to use this immune response to identify novel membrane-associated targets for CLL. Using a novel strategy, we interrogated CLL membrane-specific autologous immunoglobulin G reactivity. Our analysis unveiled lymphocyte cytosolic protein 1 (LCP1), a lymphocyte-specific target that is highly expressed in CLL. LCP1 plays a critical role in B-cell biology by crosslinking F-actin filaments, thereby solidifying cytoskeletal structures and providing a scaffold for critical signaling pathways. Small interfering RNA knockdown of LCP1 blocked migration toward CXCL12 in transwell assays and to bone marrow in an in vivo xenotransplant model, confirming a role for LCP1 in leukemia migration. Furthermore, we demonstrate that the Bruton's tyrosine kinase inhibitor ibrutinib or the PI3K inhibitor idelalisib block B-cell receptor induced activation of LCP1. Our data demonstrate a novel strategy to identify cancer membrane target antigens using humoral anti-tumor immunity. In addition, we identify LCP1 as a membrane-associated target in CLL with confirmed pathogenic significance. This clinical trial was registered at clinicaltrials.gov; study ID number: OSU-0025 OSU-0156.
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Dubovsky
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Chappell
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Harrington
authors.forename: Kitty
authors.initials: K
authors.lastname: Agrawal
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Andritsos
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Flynn
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.forename: Michael E
authors.initials: ME
authors.lastname: Paulaitis
authors.forename: Brad
authors.initials: B
authors.lastname: Bolon
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D019921:Biotinylation; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism* / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D011485:Protein Binding; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C047262:LCP1 protein, human; D008840:Microfilament Proteins; D020543:Proteome; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell