Normal and Neoplastic Growth Suppression by The Extended Myc Network

Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators (the Myc Network) that includes its obligate heterodimerization partner Max and six “Mxd proteins” (Mxd1-4, Mnt and Mga) each of which heterodimerizes with Max and largely oppose Myc’s functions. More recently, a second group of bHLH-ZIP proteins (the Mlx Network) has emerged. It is comprised of the Myc-like factors ChREBP and MondoA, which, in association with the Max-like member Mlx, regulate smaller and more functionally restricted sets of target genes, some of which are shared with Myc. Opposing ChREBP and MondoA are heterodimers comprised of Mlx and Mxd1, Mxd4 and Mnt, which also structurally and operationally link the two Networks. We discuss here the functions of these “Extended Myc Network” members with particular emphasis on the roles played by Max, Mlx and Mxd proteins in suppressing normal and neoplastic growth. These roles are complex due to the temporally- and tissue-restricted expression of Extended Myc Network proteins in normal cells, their regulation of both common and unique target genes and, in some cases, their functional redundancy.

Coexistence D’un Lymphome Lymphocytique Et D’une Leucémie Myéloïde Chronique: A Propos De Deux Observations Au Togo

Les auteurs rapportent deux cas de lymphomes lymphocytiques associés à une leucémie myéloïde chronique (LMC) au Togo. La première association est une coexistence simultanée d’une LMC avec présence du transcrit de fusion bcr-abl chez une patiente de 32 ans, au stade myélocytaire chronique, avec une polyadénopathie ayant nécessité une biopsie ganglionnaire qui a conclu à un lymphome lymphocytique. Le deuxième cas est une succession à 6 ans 5 mois d’intervalle, chez un patient de 30 ans, d’une LMC avec présence du bcr-abl et d’un chromosome Philadelphie et d’un lymphome lymphocytique. Ces deux cas sont rapprochésdiachronique des des associations d’hémopathies myéloïdes et lymphoïdes, aiguës ou chroniques. Dide la chimiothérapie mais le diagnostic est parfois simultané ; implication des oncogènes cellulaires ; plus vraisemblablement anomalie clonale de la cellule souche hématopoïétique s’exprimant de façon séquentielle ou simultanée sur les deux lignées filles. A notre connaissance, il s’agit des premières descriptions en Afrique subsaharienne.fférentes hypothèses pathogéniques sont passées en revue : responsabilité This paper reported two cases of lymphocytic lymphoma associated with chronic myeloid leukemia (CML) in Togo. The first association is a simultaneous coexistence of a CML with the presence of the transcript bcr-abl, in a 32-year-old woman, at chronic myelocytic stage with polyadenopathy required and lymph node biopsy concluded for lymphocytic lymphoma. The second is the case of a 30-year-old man who developed a lymphocytic lymphoma after 6years and 5 months of following CML. These two cases are comparable to other associations of acute or chronic myeloid and lymphoid blood malignancies that was previously published. Several pathogenic hypothesis were reviewed which takes responsibility for chemotherapy. Nevertheless, the diagnosis is sometimes simultaneous with the involvement of cellular oncogenes. This is a more likely clonal abnormality of the stem cell sequentially or concomitantly expressed in the cells on both lineages. To the best of our knowledge, these are the first descriptions in South-Saharan Africa.

Comparative Analysis Between Cellular Oncogenes and Viral Oncogenes

Carcinogenesis is a complex process that consists of multiple genetic events, leading to the activation of dominant-acting oncogenes and the cancellation of certain tumor suppressor genes functions. Previous studies on interactions between oncogenes and cells proved that viral or cellular oncogenes have a determinant role in malignant cells by supporting aberrant proliferation, epigenetic alterations, and reprogramming. After the cellular differentiation is complete, tumor suppressor genes are involved in cell regulation, by inhibiting mitogenic signaling pathways and cell cycle progression and by keeping the stability of the genome. Mutations that lead to loss of TSG function are commonly identified in various cancer types, such as lung, cervical, breast, pancreatic and colorectal cancer. The aim of this study is to specify the genetic factors involved in tumor and malignant processes and to compare the oncogene types in order to establish an evolutionary correlation between them. The analysis of cellular and viral oncogenes shows that their structure and functions are alike, which supports the idea that viral oncogenes originated from cell proto-oncogenes. This is an intensively studied field with high hopes of better understanding carcinogenesis and discovering novel therapies based on the genetic modifications that occur in malignant cells.

Cooperation of genes in HPV16 E6/E7-dependent cervicovaginal carcinogenesis trackable by endoscopy and independent of exogenous estrogens or carcinogens

Human papillomavirus (HPV) infection is necessary but insufficient for progression of epithelial cells from dysplasia to carcinoma-in situ (CIS) to invasive cancer. The combination of mutant cellular and viral oncogenes that regulate progression of cervical cancer (CC) remains unclear. Using combinations of HPV16 E6/E7 (E+), mutant Kras (mKras) (K+) and/or loss of Pten (P−/−), we generated autochthonous models of CC without exogenous estrogen, carcinogen or promoters. Furthermore, intravaginal instillation of adenoCre virus enabled focal activation of the oncogenes/inactivation of the tumor suppressor gene. In P+/+ mice, E6/E7 alone (P+/+E+K−) failed to cause premalignant changes, while mKras alone (P+/+E−K+) caused persistent mucosal abnormalities in about one-third of mice, but no cancers. To develop cancer, P+/+ mice needed both E6/E7 and mKras expression. Longitudinal endoscopies of P+/+E+K+ mice predicted carcinoma development by detection of mucosal lesions, found on an average of 23 weeks prior to death, unlike longitudinal quantitative PCRs of vaginal lavage samples from the same mice. Endoscopy revealed that individual mice differed widely in the time required for mucosal lesions to appear after adenoCre and in the time required for these lesions to progress to cancer. These cancers developed in the transition zone that extends, unlike in women, from the murine cervix to the distal vagina. The P−/−E+K+ genotype led to precipitous cancer development within a few weeks and E6/E7-independent cancer development occurred in the P−/−E−K+ genotype. In the P−/−E+K− genotype, mice only developed CIS. Thus, distinct combinations of viral and cellular oncogenes are involved in distinct steps in cervical carcinogenesis.

Loss of BRCA1 Spontaneously Induces the Tumorigenesis in Lacrimal Gland

Environmental and genetic factors exert important influences on lifespan and neoplastic transformation. We have previously shown that spontaneous tumors form frequently in mice homozygous for a full-length Brca1 deletion. In general, mutations of BRCA1 are closely associated with induction of breast and ovarian cancers but are also known to contribute to the incidence of other cancers at a low frequency. Female Brca1-mutant mice (Brca1co/coMMTV-cre) were generated by crossing Brca1 conditional knockout mice and MMTV-cre mice, and the occurrence of lacrimal gland abnormalities and tumors was followed until mice reached 18 months of age. Lacrimal gland tumors, which occur at a very low frequency in the human population (1 per 1,000,000 per year), were detected in 7 cases of Brca1co/coMMTV-cre mice (2.75%) older than 9 months of age. None of seven mice exhibited any abnormality in the mammary gland including neoplasia, suggesting lacrimal gland tumor is spontaneously and independently formed. These tumors, which were detected in seven mutant mice that displayed exophthalmoses, were malignant, originated from epithelial cells, and were identified as acinic cell carcinoma by pathological analysis. Further analysis revealed that tumorigenesis was accompanied by the accumulation of cyclin D1 and decreased expression of the cellular oncogenes, c-Myc, c-Jun, and c-Raf. Tumors also exhibited rearrangement of cytoskeletal proteins, including β-catenin, keratin 5, and vimentin, depending on tumor progression. These results suggest that BRCA1 is involved in genetic stability of the lacrimal gland, providing new insight into genomic instability in organism maintenance and tumorigenesis of the lacrimal gland.