Genes regulating the B cell receptor pathway are recurrently mutated in primary central nervous system lymphoma

Abstract

B cell receptor (BCR) signals induce differentiation, proliferation, and apoptosis of B cells. Antigenic stimulation leads to crosslinking of the BCR complex, which consists of immunoglobulin heavy and light chains, one CD79A and one CD79B subunit. As consequence of BCR stimulation, a cascade of signals is induced, activating crucial pathways like the nuclear factor-jB pathway (Fig. 1). Recently, mutations altering CD79B were detected in nodal diffuse large B cell lymphomas (DLBCL) of the activated B cell subtype, which affected BCR signaling [1]. Since primary lymphomas of the central nervous system (PCNSL) also constitute an, albeit distinct, DLBCL entity [5], we investigated whether mutations leading to BCR pathway deregulation may be involved in their pathogenesis. Mutational analysis of genes encoding crucial components of the BCR signaling cascade was performed in 25 PCNSL. Overall, 11 PCNSL (44 %) harbored a total of 15 mutations (Table 1, Suppl. Fig. 1). In all instances, wildtype sequence was also detectable. Although all mutations were protein changing, the BCR pathway remained functional, thus, still allowing BCR signaling. The mutations were not due to the process of somatic hypermutation as indicated by their position more than 2 kB downstream of transcription start [3, 6]. Mutations of the SHIP gene not reported in DLBCL or PCNSL before [7, 8] were identified in five PCNSL (20 %) and involved the phosphatase domain in two tumors. CD79B was targeted in five PCNSL (20 %). In two PCNSL, CD79B mutations involved the first ITAM (immunoreceptor tyrosinebased activation motif) tyrosine which is also targeted in nodal DLBCL [1]. ITAM mutations have been shown to increase BCR cell surface expression and to impede feedback inhibition of BCR signaling, ultimately, inducing chronic active BCR signaling [1]. In addition, mutations not yet reported were observed at other positions of the CD79B gene. CBL and BLNK were detected in one PCNSL each (4 %), while