MYC Oncogene Activity in B-Cell Lymphoma Depends on the CD19 Surface Marker

Cancer researchers specializing in B-cell lymphomas have uncovered a previously unknown relationship between the oncogene MYC and the B-cell surface receptor CD19.

MYC is a very strong proto-oncogene, and it is very often found to be upregulated in many types of cancers. The Myc protein encoded by this gene is a transcription factor that activates expression of a great number of genes through binding on consensus sequences (Enhancer Box sequences (E-boxes)) and recruiting histone acetyltransferases (HATs). It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 coactivator, it inhibits expression of Miz-1 target genes. MYC is activated upon various mitogenic signals such as Wnt, Shh, and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, MYC activation results in numerous biological effects. The protein encoded by MYC has been found to be highly resistant to chemotherapy mainly because it lacks efficient binding sites for drug compounds.

CD19 is a 95 kDa transmembrane glycoprotein with two Ig-like C2-set domains. CD19 regulates B-cell development and activation through interactions with CD21, CD22, and the B-cell receptor. CD19 polymorphisms and upregulation lead to the development of autoimmunity by promoting autoantibody production. Its downregulation is associated with the malignant phenotype in multiple myeloma.

Investigators at the University of Pennsylvania (Philadelphia, USA) worked with two different lymphoma cell lines: a MYC-induced mouse lymphoma model as well as a MYC-transformed human B-cell line.

They reported in the May 1, 2012, online edition of the Journal of Clinical Investigation that Myc levels in B-cells from CD19-deficient mice were sharply reduced. Conversely, reexpression of CD19 in mouse lymphomas with spontaneous silencing of the CD19 activator PAX5 (paired box protein-5) boosted Myc levels, expression of its key target genes, cell proliferation in vitro, and overall tumor growth in vivo. In human B-cell 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 was shown to be a major regulator of MYC-driven cancerous growth in B-cell lymphomas.

“Our research suggests ways to devise more specific therapies to selectively kill tumor cells in a subset of lymphomas,” said senior author Dr. Andrei Thomas-Tikhonenko, associate professor of pathology and laboratory medicine at the University of Pennsylvania. “We found that CD19 is absolutely required to stabilize the Myc protein. When Myc is stable and present in high levels, it fuels cancer. Patients with high levels of the Myc protein are more likely to die of lymphoma. Without CD19, there is no Myc, so controlling that on-off switch could represent a powerful tool against lymphoma.”

Related Links:
University of Pennsylvania