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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2257-2266
Number of pages10
JournalJournal of Clinical Investigation
Volume122
Issue number6
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

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B-Lymphocytes
Lymphoma
Immunoreceptor Tyrosine-Based Activation Motif
PAX5 Transcription Factor
Genetic Translocation
Protein Stability
B-Cell Lymphoma
Growth
Phosphatidylinositol 3-Kinases
Genes
Neoplasms
Transcription Factors
Cell Proliferation
Cell Line
Messenger RNA
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis. / Chung, Elaine Y. L.; Psathas, James N.; Yu, Duonan; Li, Yimei; Weiss, Mitchell J.; Thomas-Tikhonenko, Andrei.

In: Journal of Clinical Investigation, Vol. 122, No. 6, 01.06.2012, p. 2257-2266.

Research output: Contribution to journalArticle

Chung, Elaine Y. L. ; Psathas, James N. ; Yu, Duonan ; Li, Yimei ; Weiss, Mitchell J. ; Thomas-Tikhonenko, Andrei. / CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 6. pp. 2257-2266.
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