We have determined the sequence of the normal human c-myc gene and compared it to portions of a c-myc gene that has been translocated into the immunoglobulin heavy chain locus in a Burkitt lymphoma cell.
These data therefore suggest that EBV can contribute to BL through at least two avenues: an EBER-dependent mechanism that enhances tumorigenic potential independent of a direct effect on apoptosis, and a second mechanism, mediated by an as-yet-unidentified EBV gene(s), that offsets the proapoptotic consequences of deregulated c-MYC in BL.
We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL.
It has been known for many years that the fundamental transforming event in BL is the translocation of the MYC gene, and the events that bring about this translocation and those that allow cells to survive with the constitutive expression of MYC have been the subject of intense investigation.
Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma.
These results and our finding of recurrent PI3K pathway activation in human BL indicate that deregulated c-MYC and PI3K activity cooperate in BL pathogenesis.
In Burkitt's lymphoma (BL) cells characteristic chromosomal translocations juxtapose the MYC oncogene to one of the three immunoglobulin (IG) gene loci.
We find that, during in vitro culture, Ramos mutates the c-MYC allele that is translocated into the IgH locus whilst leaving the untranslocated c-MYC and other control genes essentially unaffected.
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.
This unexpected, frequent occurrence of clustered mutations in the second exon of the MYC gene suggests a role for the mutated MYC proteins in the pathogenesis of Burkitt's lymphoma, possibly through altered interactions of this domain with other cellular factors.
We analyzed the Burkitt's lymphoma line BL64 in which a reciprocal translocation joins the immunoglobulin kappa light-chain locus on chromosome 2 to the c-myc gene on chromosome 8.
These results support a model in which c-myc oncogene activation in Burkitt's lymphoma occurs by disruption of a normal transcriptional control mechanism in which the c-myc protein is itself involved.
MYC gene alterations in diffuse large B-cell lymphomas and in B-cell lymphomas, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma are frequently associated with BCL2 or/and BCL6 translocations conferring a very aggressive behavior.
Here we report that two common mutant MYC alleles derived from human Burkitt's lymphoma uncouple proliferation from apoptosis and, as a result, are more effective than wild-type MYC at promoting B cell lymphomagenesis in mice.
The same approach identifies MYC and multiple Myc targets as a preferential target of down-regulated miRNAs in human Burkitt lymphoma, a pathology characterized by translocated MYC oncogenes.
To assess the functional consequences of MYC binding, the ChIP-Seq data were supplemented with siRNA- mediated knock-downs of MYC in BL cell lines followed by gene expression profiling.
Therefore, an understanding of the mechanism by which overexpressed c-Myc contributes to the development of Burkitt's lymphoma requires the identification of additional c-Myc target genes.
The t(8;14)(q24;q32), involving MYC gene (8q24) and the immunoglobulin heavy chain (IgH) locus (14q32), represents about 75% of all translocations in Burkitt's lymphoma (BL).
Abnormalities of the MYC oncogene on chromosome 8 are characteristic of Burkitt lymphoma and other aggressive B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL).
Whereas TFE3 is typically fused to partner proteins in subsets of renal tumors, we found that wild-type, unfused TFE3 stimulates clonogenic growth in a cell-based assay, suggesting that dysregulated expression, rather than altered function of TFEB or TFE3 fusions, may confer neoplastic properties, a mechanism reminiscent of MYC activation by promoter substitution in Burkitt's lymphoma.
MYC rearrangement is a recurring genetic abnormality in several aggressive B-cell lymphomas including: Burkitt lymphoma, diffuse large B-cell lymphoma; B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma; rare de novo acute lymphoblastic lymphoma/leukemia, transformed follicular lymphoma, and plasmablastic lymphoma.