These data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumour cells to evade p53 action during lymphomagenesis.
Rearrangements involving the 1p36 chromosomal region occur frequently in NHL, suggesting the existence of tumor suppressor gene(s) that are important in lymphomagenesis. p73 is closely related to the tumor suppressor p53 and maps to the chromosome 1p36 region.
Using a mouse model harboring primary, genetically modified myc-driven lymphomas, we show that disruption of apoptosis downstream of p53 by Bcl2 or a dominant-negative caspase 9 confers-like p53 loss-a selective advantage, and completely alleviates pressure to inactivate p53 during lymphomagenesis.
These data demonstrate that unrepaired O6mG lesions act cooperatively with the reduced p53 dose and lead to lymphomagenesis in p53+/- mice, but AGT overexpression and rapid removal of O6mG adducts is protective.
Although the precise role of the p53 point mutation in leukemogenesis remains to be clarified, the establishment of an NK leukemia cell line with a p53 point mutation could be valuable in the study of leukemogenesis.
In this study, immunoglobulin variable (Ig V) region genes, c-myc re-arrangement and sequence and p53 status were analyzed in clones derived from a Burkitt's lymphoma cell line (LAM) in which it was previously demonstrated that Epstein-Barr virus (EBV) infection occurred late during lymphomagenesis.
We conclude that, (1) p53 mutations are infrequent at diagnosis but tend to be associated with poor clinical outcome; (2) RAS and p21 mutations may not be involved in the pathogenesis of T-ALL; (3) not only frequent alterations of p16 and p15 genes but also methylation of p16 gene are involved in initiating the leukemogenesis of T-ALLs, and (4) these 5 genes are independently involved in T-ALL.
Collectively, these results show that mutations of p53 gene in BLV-infected cattle with lymphosarcoma can potentially alter its physiological function and may play an important role in BLV-induced leukemogenesis.
These results suggest that HPV16E6 could stimulate p53 protein degradation in mouse cells and induced the lymphomagenesis in a manner indistinguishable from p53 deficiency.
Relevant strains of genetically engineered mice, including bcl-2-Ig and E mu-myc transgenic mice and p53 knockout mice, have been used to prospectively examine the regulation of apoptotic cell death by these genes, individually and in combination, and their contribution to in vivo lymphomagenesis.
The high frequency of p53 mutation in NHL B cell lines and the relatively low frequency of p53 mutations in fresh lymphoma tissue suggests that p53 gene alteration may play a role in lymphomagenesis and/or disease progression in a subset of B cell lymphomas and that the p53 mutation conveys a proliferative advantage on lymphoma cells that permits their in vitro growth.
The genetic mechanisms underlying the genesis of low-grade mucosa-associated lymphoid tissue (MALT) lymphomas and their transformation into high-grade lymphoma are poorly understood. p53 inactivation, commonly caused by mutation and allele loss, has been shown to play an important role in the early development and/or the late disease progression of many human tumors including lymphoid malignancies and, thus, may also be important in MALT lymphomagenesis.