CD19 is a major B cell receptor–independent activator of MYC-driven B-lymphomagenesis
Elaine Y. Chung, … , Mitchell J. Weiss, Andrei Thomas-Tikhonenko
Elaine Y. Chung, … , Mitchell J. Weiss, Andrei Thomas-Tikhonenko
Published May 1, 2012
Citation Information: J Clin Invest. 2012;122(6):2257-2266. https://doi.org/10.1172/JCI45851.
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CD19 is a major B cell receptor–independent activator of MYC-driven B-lymphomagenesis

Abstract

PAX5, a B cell–specific transcription factor, is overexpressed through chromosomal translocations in a subset of B cell lymphomas. Previously, we had shown that activation of immunoreceptor tyrosine-based activation 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-GSK3β axis. Consequently, MYC levels in B cells from CD19-deficient 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 overall 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.

Authors

Elaine Y. Chung, James N. Psathas, Duonan Yu, Yimei Li, Mitchell J. Weiss, Andrei Thomas-Tikhonenko

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Figure 1

PAX5 regulates c-MYC protein levels.

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PAX5 regulates c-MYC protein levels. All panels represent immunoblotting...
All panels represent immunoblotting analyses of proteins indicated. Actin was used as a loading control. (A) P493-6 cells either untreated (0 hours) or treated with Dox for indicated intervals prior to harvesting. (B) MYC5 cells infected with either the empty MIGR1 vector (GFP) or PAX5-MIGR1 (PAX5). Protein lysates were prepared 24 and 48 hours after infection. (C) Protein lysates were obtained from MYC tumors samples described previously (27). Prior to implantation, MYC5 cells were infected with either the empty MIGR1 vector or PAX5ERMIGR1 (PAX5ER). (D) P493-6 cells electroporated using various anti-PAX5 (PAX5) or control (Ctrl) siRNAs. (E) P493-6 cells were electroporated (e/p) with 1 μM of either control or anti-PAX5 siRNA, and lysates were harvested 24 and 48 hours after electroporation.