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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Research Article Oncology

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 3

CD19 regulates MYC protein expression through the PI3K/AKT pathway.

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CD19 regulates MYC protein expression through the PI3K/AKT pathway. All ...
All panels represent immunoblotting analyses of proteins that belong to the CD19/PI3K pathway. Actin was used as a loading control. (A) P493-6 cells electroporated 24 hours prior to harvesting with 1 μM of control or anti-CD19 siRNA. (B) The same cells treated with 10 μM of PI3K inhibitor LY29004 or vehicle alone (ethanol) for 1 hour. (C) Splenic B cells pretreated with the same reagents for 0.5 hours. (D) MYC5 cells transduced with either empty retroviral vector (neo) or retroviruses expressing constitutively active forms of Akt1/2 (AKTmyr). Protein lysates were additionally probed with antibodies against MYC residues Thr-58 and Ser-62. (E) P493-6 cells electroporated 48 hours prior to harvesting with increasing concentrations of control or anti-GSK3β siRNA. (F) MYC5 cells expressing GFP or PAX5 were additionally transduced with either empty vector, WT MYC, or the T58A variant. Transduced cells were immunoblotted for MYC, and MYC protein levels in PAX5-transduced cells were compared with those in GFP-transduced cells. Note that the T58A variant has the Py-tag and thus migrates slower in SDS-PAGE gels. (G) MYC5 cells expressing GFP or CD19 from Figure 2B were additionally transduced with either empty vector or the PTEN-encoding retrovirus (PTEN).