HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Oncogenic mechanisms in Burkitt lymphoma.

Abstract
Burkitt lymphoma is a germinal center B-cell-derived cancer that was instrumental in the identification of MYC as an important human oncogene more than three decades ago. Recently, new genomics technologies have uncovered several additional oncogenic mechanisms that cooperate with MYC to create this highly aggressive cancer. The transcription factor TCF-3 is central to Burkitt lymphoma pathogenesis. TCF-3 is rendered constitutively active in Burkitt lymphoma by two related mechanisms: (1) somatic mutations that inactivate its negative regulator ID3, and (2) somatic mutations in TCF-3 that block the ability of ID3 to bind and interfere with its activity as a transcription factor. TCF-3 is also a master regulator of normal germinal center B-cell differentiation. Within the germinal center, TCF-3 up-regulates genes that are characteristically expressed in the rapidly dividing centroblasts, the putative cell of origin for Burkitt lymphoma, while repressing genes expressed in the less proliferative centrocytes. TCF-3 promotes antigen-independent (tonic) B-cell-receptor signaling in Burkitt lymphoma by transactivating immunoglobulin heavy- and light-chain genes while repressing PTPN6, which encodes the phosphatase SHP-1, a negative regulator of B-cell-receptor signaling. Tonic B-cell-receptor signaling sustains Burkitt lymphoma survival by engaging the PI3 kinase pathway. In addition, TCF-3 promotes cell-cycle progression by transactivating CCND3, encoding a D-type cyclin that regulates the G1-S phase transition. Additionally, CCND3 accumulates oncogenic mutations that stabilize cyclin D3 protein expression and drive proliferation. These new insights into Burkitt lymphoma pathogenesis suggest new therapeutic strategies, which are sorely needed in developing regions of the world where this cancer is endemic.
AuthorsRoland Schmitz, Michele Ceribelli, Stefania Pittaluga, George Wright, Louis M Staudt
JournalCold Spring Harbor perspectives in medicine (Cold Spring Harb Perspect Med) Vol. 4 Issue 2 (Feb 01 2014) ISSN: 2157-1422 [Electronic] United States
PMID24492847 (Publication Type: Journal Article, Review)
Chemical References
  • CCND3 protein, human
  • Cyclin D3
  • Phosphoinositide-3 Kinase Inhibitors
  • Transcription Factor 3
Topics
  • Burkitt Lymphoma (drug therapy, genetics)
  • Cyclin D3 (genetics)
  • Genes, myc (genetics)
  • Germinal Center (physiology)
  • Humans
  • Mutation (genetics)
  • Oncogenes (genetics)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphoinositide-3 Kinase Inhibitors
  • Signal Transduction (physiology)
  • Transcription Factor 3 (genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: