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.