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.