HASSAN JUMAA (ULM)
IMMUNOGLOBULIN LC ALLELE IGLV3-21*01 IS AN INHERITED RISK FACTOR
FOR POOR-PROGNOSIS CLL
The prognosis and response to therapy of chronic lymphocytic leukemia (CLL) is associated
with the mutational status of the B-cell receptor (BCR) and various genetic aberrations. We
proposed cell autonomous BCR signaling as a unifying pathogenic mechanism in CLL and
confirmed this hypothesis in exemplary crystallographic studies. Importantly, we showed that
homotypic BCR-BCR interaction and subsequent cell autonomous signaling in distinct CLL
cases is induced upon acquisition of a specific mutation (referred to as R110) in light chains
(LC) containing the IGLV3-21 segment. By developing mutation-specific antibodies, we
screened for IGLV3-21R110-expressing CLL cases and found that they represent a distinct CLL
subtype with genetic predisposition determined by a specific IGLV3-21 allele. In fact, we found
that expression of IGLV3-21R110 is exclusively associated with allele IGLV3-21*01, which
defines a large CLL subtype with poor prognosis based on a specific immunopathogenic
mechanism. Furthermore, we found that allele IGLV3-21*01 is a genetic risk factor for
development of high-risk CLL because a single point mutation is sufficient to enable homotypic
BCR-BCR interaction and activate autonomous signaling. These findings permit identification
of healthy individuals at risk for CLL as well as facilitate convenient characterization of IGLV3-
21R110-expressing CLL, thereby setting the first step for preventive treatment.