As additional antisense molecules targeting oncogenes involved in lymphomas become available, it will be possible to combine them with AO to enhance their efficacy, either targeting the same gene at two sites or more a combination of genes (for example, BCL-2 and MYC in Burkitt's lymphoma).
Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases.
This facilitates survival of eBL tumor cells with the IGH/MYC chromosomal translocation and promotes MYC-induced cell cycle progression, initiating eBL lymphomagenesis.
We analyzed 74 adult gray zone and 10 reference pediatric BL using immunohistochemistry (Ki-67, CD10, bcl2, bcl6) and fluorescence in situ hybridization (FISH) for MYC, BCL2, and BCL6 breakpoints.
We have examined the position of the chromosomal breakpoint relative to the human c-myc gene (MYC) and the presence of other structural alterations of the same locus in 19 fresh samples of Burkitt lymphoma (BL) and 13 BL-derived cell lines.
Deregulated c-myc expression, as a consequence of translocation of the c-myc gene to one of the immunoglobulin loci, appears to play an important role in the pathogenesis of several B-cell tumors, including Burkitt's lymphoma, mouse plasmacytoma and rat immunocytoma.
We found that the most 3' enhancer region (MHS4) activated the c-myc promoter by 46-fold in the Raji Burkitt's lymphoma cell line, and it was the most active enhancer in these cells.
We have analyzed the type of MYC/IG heavy-chain locus (IGH) rearrangement present in 15 patients affected by t(8;14)-positive primary Burkitt's lymphoma or acute lymphoblastic leukemia of the L3 type in an attempt to map in detail the locations of the chromosome 8 and chromosome 14 breakpoints.
A high Ki-67 proliferation index and positive bcl-2 staining (on cytospin slides or cell block material) of cases not conforming to typical Burkitt lymphoma morphology should prompt FISH analysis for c-MYC and/or IGH-BCL2 rearrangements to identify DHL, particularly if tissue biopsy is not expected.
In the Burkitt's lymphoma (BL) cell line BL67 the first exon of the c-myc gene is fused to the mu-switch region of the immunoglobulin heavy-chain gene (IgH).
Chromosomal translocations involving MYC at 8q24 are found in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLU).
Here, we report sAJM589, a novel small molecule Myc inhibitor, identified from a PCA-based high-throughput screen. sAJM589 potently disrupts the Myc-Max heterodimer in a dose dependent manner with an IC<sub>50</sub> of 1.8 ± 0.03 μM. sAJM589 preferentially inhibits transcription of Myc target genes in a Burkitt lymphoma cell model, P493-6.