The MDM2 oncogene overexpression in chronic lymphocytic leukemia and low-grade lymphoma of B-cell origin

Abstract

The expression of the murine double minute-2 (MDM2) gene, the product of which binds to and inactivates p53, was studied in 60 patients with B-cell chronic lymphocytic leukemia (B-CLL) or non-Hodgkin's lymphoma (B-NHL). Northern blot analysis showed that the level of MDM2 gene expression was low in normal human B-cells, whereas 17 of the patients (28.3%) with B-CLL or NHL had more than 10-fold higher levels of MDM2 gene expression than that observed in normal B cells. Immunohistochemical analysis confirmed MDM2 overexpression at the cellular protein level. MDM2 gene overexpression was found more frequently in patients with the low-grade type of lymphoma (56.5%) than in those with intermediate-/high-grade types (10.8%) (P = .001). Moreover, MDM2 overexpression was found significantly more frequently in patients at advanced clinical stages. Simultaneous analysis of p53 gene mutation showed that three patients had both MDM2 gene overexpression and p53 gene mutation. The results of the present study suggest that MDM2 gene overexpression may play an important role in the tumorigenicity and/or disease progression of CLL and low-grade lymphomas of B-cell origin.

mdm2 mRNA Level is a Prognostic Factor in Soft Tissue Sarcoma

“…In numerous tumor cell lines and malignant tumors, particularly sarcomas, the human MDM2 protein overexpression is a characteristic feature (28) which can be correlated to poor prognosis (7,29). However, overexpression may occur independently of gene amplification and might correlate with an increased transcription and/ or a different translation efficiency of human mdm2 transcripts (30)(31)(32)(33)(34)(35). Occurrence of different mRNA transcript levels and splice products in malignant tumors is well described (31,36,37), but only recently was an impact on tumor behavior and prognosis uncovered (38,39).…”

MDM2 SNP309 promoter polymorphism, an independent prognostic factor in chronic lymphocytic leukemia

“…A characteristic feature is a poor response to DNA‐damaging therapeutics, indicating the importance of an intact and a functional p53 pathway to induce apoptosis (5–7). Another mode of p53 dysfunction is overexpression of the MDM2 (murine double minute 2) protein that negatively regulates the stability of p53 (8) and thus may play a role in disease progression of B‐CLL (9). A single nucleotide polymorphism (SNP309, rs2279744), resulting in either a T‐ or G‐allele, in the first intron of the core promoter region of the MDM2 gene affects binding of the transcription factor Sp1.…”

Impact of trisomy 12, del(13q), del(17p), and del(11q) on the immunophenotype, DNA ploidy status, and proliferative rate of leukemic B‐cells in chronic lymphocytic leukemia

“…Thus, B‐CLL patients with a normal karyotype or 13q‐ alone show a significantly better outcome than those showing trisomy 12, while 11q‐ and 17p‐ are associated with a poor outcome (5, 13–16). Several of these chromosome defects are known to target genes that play a key role in the regulation of cell proliferation and/or survival such as P53 (1), RB (1), CYCLIN D 2, CDK 4, and MDM 2 (17–19), and the proliferative rate of neoplastic B‐cells as evaluated by the peripheral blood (PB) lymphocyte doubling time is known to represent a powerful tool for the classification and prognostic stratification of B‐CLL (20, 21). In turn, recent studies have shown that the presence of different genetic abnormalities is associated with specific immunophenotypic profiles in both acute leukemia (22) and multiple myeloma (23), such patterns being useful for the immunophenotypic screening of the underlying genetic abnormalities.…”