SIGNIFICANCE: Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer.
Additionally, PTEN negatively correlated with p53 expression in FL and CGB DLBCL, whereas NF-κB negatively correlated with WWP2 in GCB DLBCL, but positively associated with PTEN in RFH and c-Myc in BL.
We verified that the oncogenic effect of iASPP on Burkitt lymphoma is TAp63 dependent rather than p53 and confirmed that the interaction between CDK1 and iASPP enhanced the inhibitory effect of iASPP on p53 and TAp63.
Combined loss of p53 induction and function due to miRNA-mediated regulation of ATM and NLK, together with the upregulation of TFAP4, may be a central role for human miRNAs in eBL oncogenesis.
INZ(c) treatment decreased c-Myc expression at both mRNA and protein level, and suppressed c-Myc transcriptional activity in human Burkitt's lymphoma Raji cells with mutant p53.
We investigated TP53 pathway disruption in paediatric BL patient samples (n = 30) by studying MDM4, MDM2, and CDKN1A (p21) protein and mRNA expression; TP53 mutations; TP53 protein expression; and gene copy number abnormalities.
In order to better understand the mechanisms by which chemoresistance is mediated, non-hodgkin's lymphoma (NHL) patients overexpressing p53 mutant protein and resistant to CHOP chemotherapy, NHL patients without p53 overexpression and a Burkitt's lymphoma Raji cell line with p53 overexpression have been evaluated using fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH).
Mutation of the p53 tumor suppressor is associated with disease progression, therapeutic resistance, and poor prognosis in patients with lymphoid malignancies and can occur in approximately 50% of Burkitt lymphomas.
Our results showed that BL cell lines have variable response to DNA-damaging agents that cannot be correlated exclusively with p53 mutation or survivin expression suggesting that p53-independent transactivation may play a role in apoptosis induced by DNA-damaging agents.
Here we show that chloroquine, a drug that activates the stress-responsive Atm-p53 tumor-suppressor pathway, preferentially enhances the death of Myc oncogene-overexpressing primary mouse B cells and mouse embryonic fibroblasts (MEFs) and impairs Myc-induced lymphomagenesis in a transgenic mouse model of human Burkitt lymphoma.
Similarly, human Burkitt lymphomas with wild-type p53 and overexpression of Hdm2 are highly sensitive to proteasome inhibitors, unless p53 levels are reduced using the HPV-E6 ubiquitin ligase.
Activation of endogenous wt p53 in BLs and lymphoblastoid cell lines led to the induction of SAP and this was inhibited by the specific p53 inhibitor pifithrin-alpha.
The molecular biological characteristics of Burkitt lymphoma (BL), in addition to the presence of the Epstein-Barr virus (EBV) in some forms, relies on well-characterized alterations, such as MYC translocations and TP53 inactivations.
Immunohistochemical overexpression of p53 protein was found in 21% of NHL patients, with the highest incidence of p53 immunoreactivity in cases of Burkitt's lymphoma, follicle center lymphoma grade III, and diffuse large B-cell lymphoma.