To validate the role of gene signatures associated with MYC in human tumorigenesis, we examined the expression of human homologs in 273 published human lymphoma microarray datasets in Affymetrix U133A format.
There were 47 DTHLs, 36 cases with MYC and BCL2 and/or BCL6 extra signals (ES) and/or rearrangements (ES group, excludes DTHLs), 9 with MYC rearrangements only (single-hit lymphoma), and 95 with no MYC abnormalities (NM).
Specifically, following regulatory network analysis in human B-cells, we identify a novel role of the STK38 kinase as a regulator of MYC activity and a candidate target for abrogating tumorigenesis in MYC-addicted lymphoma.
Isolated BCL2 and MYC rearrangements were not predictive of outcome in our patients as a whole, but only in those with the germinal center subtype of lymphoma.
We identify lymphoma subtype-specific enhancers in the MYC locus that are silenced in lymphomas with MYC-activating rearrangements and are associated with germline polymorphisms that alter lymphoma risk.
We observed that in vivo phosphorylation of Thr-58 was absent in a lymphoma cell line with a mutant MYC allele containing a missense mutation flanking codon 58.
Real-time polymerase chain reaction showed C-MYC mRNA expression in lymphoma-type and acute-type samples were significantly higher than in smoldering-type (P<0.01).
Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G(1) arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines.
MYC upregulation simultaneously sensitizes cells to apoptosis and activated lymphocytes and lymphoma cells have pro-survival attributes that allow MYC-driven proliferation to prevail.
Furthermore, MYC possesses nontranscriptional functions other than transcriptional controls on genes regulating cell growth and may also influence the lymphoma microenvironment.
Our method can quantify amounts of MYC oncoprotein and B cell lymphoma protein-2 (BCL2) in Burkitt's and follicular lymphoma; identify changes in activation of extracellular signal-related kinases-1 (ERK1) and ERK2, mitogen-activated kinase-1 (MEK), signal transducer and activator of transcription protein-3 (STAT3) and STAT5, c-Jun N-terminal kinase (JNK) and caspase-3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure an unanticipated change in the phosphorylation of an ERK2 isomer in individuals with CML who responded to imatinib; and detect a decrease in STAT3 and STAT5 phosphorylation in individuals with lymphoma who were treated with atorvastatin.
To examine how the MYC and K-ras(G12D) oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma.
Patients with both MYC and BCL2 CNA had similar outcomes to those with classic double hit lymphoma or protein double expression lymphoma (MYC and BCL2/BCL6 coexpression).
Patients with abdominal nodal disease had inferior lymphoma specific survival (p=0.04) and presented with higher age adjusted IPI (p<0.001), lactate dehydrogenase (p<0.001) and more often advanced stage (p<0.001), bulky disease (p<0.001), B-symptoms (p<0.001), and double expression of MYC and BCL2 (p=0.02) compared to patients without nodal abdominal involvement, but less often extranodal involvement (p<0.02).
Mutation of Thr58 in lymphoma thus escapes this regulation resulting in accumulation of c-Myc protein, likely as part of the tumor progression.(Blood.2000;95:2104-2110)
Similar to endemic and sporadic Burkitt's lymphoma, monoclonal B-lymphoma subsets were found to be infected with Epstein-Barr virus (EBV) or have c-myc gene rearrangements, suggesting a role for EBV infection or chromosomal translocation in a subset of AIDS NHLs.