CD19 is a major B cell receptor--independent activator of MYC-driven B-lymphomagenesis

PAX5, a B cell-specific transcription factor, is overexpressed through chromosomal translocations in a sub-set of B cell lymphomas. Previously, we had shown that activation of immunoreceptor tyrosine-based activa-tion motif (ITAM) proteins and B cell receptor (BCR) signaling by PAX5 contributes to B-lymphomagenesis. However, the effect of PAX5 on other oncogenic transcription factor-controlled pathways is unknown. Using a MYC-induced murine lymphoma model as well as MYC-transformed human B cell lines, we found that PAX5 controls c-MYC protein stability and steady-state levels. This promoter-independent, posttranslational mechanism of c-MYC regulation was independent of ITAM/BCR activity. Instead it was controlled by another PAX5 target, CD19, through the PI3K-AKT-GSK3 β axis. Consequently, MYC levels in B cells from CD19-defi-cient mice were sharply reduced. Conversely, reexpression of CD19 in murine lymphomas with spontaneous silencing of PAX5 boosted MYC levels, expression of its key target genes, cell proliferation in vitro, and over-all tumor growth in vivo. In human B-lymphomas, CD19 mRNA levels were found to correlate with those of MYC-activated genes. They also negatively correlated with the overall survival of patients with lymphoma in the same way that MYC levels do. Thus, CD19 is a major BCR-independent regulator of MYC-driven neoplastic growth in B cell neoplasms.
Introduction The concept of oncogene addiction (1) is particularly well validated in hematological malignancies. 'Liquid' tumors are thought to depend on fewer genetic alterations and thus be more sensitive to [...]