ABSTRACT
Accumulating evidence support the view that the monoclonal B-cell receptor (BCR) of
leukemic lymphocytes plays a crucial role in the selection and survival of chronic
lymphocytic leukemia (CLL) cells (1,2). At the molecular level, malignant cells preferentially
use specific immunoglobulin heavy chain variable (IGHV) genes; in more than half of the
cases, they carry somatic mutations in the IGHV genes (3,4); over 20% of the cases express
highly homologous (“stereotyped”) complementarity-determining region 3 (CDR3) sequen-
ces (5-12). At the functional level, CLL cells show a heterogeneous pattern of responsiveness
to BCR cross-linking, and some of them resemble anergic lymphocytes (1,2). To better define
the molecular framework of antigenic stimulation in CLL cells, we will herein dissect step by
step the mechanisms of regulation of BCR activity: first, we will analyze the nature of the
membrane-associated BCR chains; second, we will discuss the BCR signal transduction
pathways in normal and malignant B lymphocytes; third, we will describe distinct BCR
coreceptors and costimulatory molecules, and; finally, we will propose a model where all the
described BCR regulatory molecules concur to modulate antigen responsiveness or anergy in
clinically different CLL subsets.
