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PAX5, a B cell-specific transcription factor, is overexpressedthrough chromosomal translocations in a subset of B cell lymphomas. Previously, we hadshown that activation of immunoreceptor tyrosine-based activation motif (ITAM) proteinsand B cell receptor (BCR) signaling by PAX5 contributes to B-lymphomagenesis. However,the effect of PAX5 on other oncogenic transcription factor-controlled pathways isunknown. Using a MYC-induced murine lymphoma model as well as MYC-transformed human Bcell lines, we found that PAX5 controls c-MYC protein stability and steady-state levels.This promoter-independent, posttranslational mechanism of c-MYC regulation wasindependent of ITAM/BCR activity. Instead it was controlled by another PAX5 target,CD19, through the PI3K-AKT-GSK3β axis. Consequently, MYC levels in B cellsfrom CD19-deficient mice were sharply reduced. Conversely, reexpression of CD19 inmurine lymphomas with spontaneous silencing of PAX5 boosted MYC levels, expression ofits key target genes, cell proliferation in vitro, and overall tumor growth in vivo. Inhuman B-lymphomas, CD19 mRNA levels were found to correlate with those of MYC-activatedgenes. They also negatively correlated with the overall survival of patients withlymphoma in the same way that MYC levels do. Thus, CD19 is a major BCR-independentregulator of MYC-driven neoplastic growth in B cell neoplasms.

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