The goal of this review is to describe the biological and clinical implications associated with the analysis of the immunoglobulin (also known as B-cell receptor) expressed on the surface of the tumor cells of chronic lymphocytic leukemia (CLL). Analysis of the surface immunoglobulin structure, levels, and signaling characteristics has regularly improved our understanding of this leukemia for the last +20 years since the identification of two subsets with unmutated tumor immunoglobulin (U-CLL) and bad prognosis or mutated immunoglobulins (M-CLL) and good prognosis. In this review, the authors summarize how analysis of the tumor immunoglobulin informs origin, maintenance, progression, current therapy choice, and prognosis of CLL while providing clues for future investigations.

The B-cell receptor (BCR) is essential to the behavior of the majority of normal and neoplastic mature B cells. The identification in 1999 of the two major CLL subsets expressing unmutated immunoglobulin (Ig) variable region genes (U-IGHV, U-CLL) of pre-germinal center origin and poor prognosis, and mutated IGHV (M-CLL) of post-germinal center origin and good prognosis, ignited intensive investigations on structure and function of the tumor BCR. These investigations have provided fundamental insight into CLL biology and eventually the mechanistic rationale for the development of successful therapies targeting BCR signaling. U-CLL and M-CLL are characterized by variable low surface IgM (sIgM) expression and signaling capacity. Variability of sIgM can in part be explained by chronic engagement with (auto)antigen at tissue sites. However, other environmental elements, genetic changes, and epigenetic signatures also contribute to the sIgM variability. The variable levels have consequences on the behavior of CLL, which is in a state of anergy with an indolent clinical course when sIgM expression is low, or pushed towards proliferation and a more aggressive clinical course when sIgM expression is high. Efficacy of therapies that target BTK may also be affected by the variable sIgM levels and signaling and, in part, explain the development of resistance.