MYC translocation has been associated with tumor progression in multiple myeloma but has only rarely been previously reported in plasmablastic lymphoma.
MYC activation, whether assessed by gene-expression signature or IHC, is associated with hyperdiploid MM and shorter survival even in tumors that are not proliferative.
MYC rearrangements are frequent in plasmablastic lymphomas, advanced plasma cell myelomas and a subgroup of diffuse large B-cell lymphomas, but their presence in ALK-positive large B-cell lymphomas is unknown.
A complex translocation has interrupted the third exon of the c-myc gene in human plasma cell myeloma tumor cells and a derivative cell line (NCI-H929).
As proof of concept, we identified a low micromolar potency molecule (compound 30666) that inhibited immunoglobulin production by MM cells and blocked expression of an array of IgH translocation-induced oncogenes (CCND1, FGFR3/MMSET, and MYC) in MM and NHL cell lines.
As such, the Ig and MYC loci are key players in the myeloma genome and including these in any genomic studies is key to understanding the relationship with other abnormalities.
Cancers like multiple myeloma (MM), which display elevated activity in key translation regulatory nodes, such as the PI3K/mammalian target of rapamycin and MYC-eukaryotic initiation factor (eIF) 4E pathways, are predicted to be particularly sensitive to therapeutic strategies that target this process.
Clinical activity of lenalidomide relies on degradation of Ikaros and the consequent reduction in IRF4 expression, both required for myeloma cell survival and involved in the regulation of MYC transcription.
Collectively, this study shows a novel mechanism that leads to increased c-MYC levels and enhanced proliferation of t(4;14) MM, and potentially other cancers with high MMSET expression.
Consistent with these findings in mice, more frequent MYC rearrangements, elevated levels of MYC mRNA, and MYC target genes distinguish human patients with multiple myeloma from individuals with monoclonal gammopathy, implicating a causal role for MYC in the progression of monoclonal gammopathy to multiple myeloma.
Consistent with these observations, in vivo blockade of CD28-CD80/CD86 in the Vk*MYC murine myeloma model sensitizes MM cells to chemotherapy and significantly reduces tumor burden.
Ex vivo pharmacodynamic analyses demonstrated that the combination of JQ1 and ricolinostat led to significantly lower MM cell proliferation and increased apoptosis and diminished expression of c-MYC and BCL-2.
Finally, measuring the levels of 2-HG in the BM supernatant and peripheral blood plasma from patients with precursor PC malignancies such as smoldering MM (SMM) demonstrates that relatively elevated levels of 2-HG are associated with higher levels of c-MYC expression in the BM clonal PCs and with a subsequent shorter time to progression (TTP) to MM.
Further studies are needed to delineate the functional relevance of HIF, MYC, and the HIF-MYC collaboration in MM and other malignancies, also integrating the tumor microenvironment and the cellular context.
Furthermore, promoter derepression of TAZ expression sensitizes MM cell lines through a reciprocal reduction in MYC expression using additional therapeutics such as bortezomib, trichostatin A, and panobinostat.
Here, we show potent anti-myeloma activity of macrophage-activating immunotherapy (αCD40+CpG) that resulted in prolongation of progression-free survival (PFS) and overall survival (OS) in an immunocompetent, preclinically validated, transplant-based model of multidrug-resistant, relapsed/refractory myeloma (t-Vκ*MYC).