Melanoma Research Today is a free monthly online journal that collates and summarizes the latest research about Melanoma, including details on identification, causes, prevention, treatment. | ||||||
|
DHODH modulates transcriptional elongation in the neural crest and melanoma.White RM, Cech J, Ratanasirintrawoot S, Lin CY, Rahl PB, Burke CJ, Langdon E, Tomlinson ML, Mosher J, Kaufman C, Chen F, Long HK, Kramer M, Datta S, Neuberg D, Granter S, Young RA, Morrison S, Wheeler GN, Zon LI Stem Cell Program and Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation. Published 24 March 2011 in Nature, 471(7339): 518-22. Articles on Melanoma published 24 March 2011: The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature, 471(7339): 513-7. The most common mutation in human melanoma, BRAF(V600E), activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway. BRAF(V600E) mutations are also present in benign melanocytic naevi, highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes. For certain amplifications, the large number of ... [Abstract] [Full-text] Articles on Melanoma published 22 March 2011: Optical coherence tomography enhanced depth imaging of choroidal tumors. Am J Ophthalmol, 151(4): 586-593.e2. Ultrasound biomicroscopic imaging of iris melanoma: a clinicopathologic study. Am J Ophthalmol, 151(4): 579-585.e1. Articles on Melanoma published 23 February 2011: Multiple antimelanoma potential of dry olive leaf extract. Int J Cancer, 128(8): 1955-65. Various constituents of the olive tree (Olea europaea) have been traditionally used in the treatment of infection, inflammation, prevention of chronic diseases, cardiovascular disorders and cancer. The anticancer potential of dry olive leaf extract (DOLE) represents the net effect of multilevel interactions between different biologically active compounds from the extract, cancer cells and conventional therapy. In this context, it was of primary interest to evaluate the influence of DOLE on ... [Abstract] [Full-text] Plasma levels of polychlorinated biphenyls and risk of cutaneous malignant melanoma: a preliminary study. Int J Cancer, 128(8): 1872-80. A number of epidemiologic studies have suggested that exposure to polychlorinated biphenyls (PCB) and other organochlorine compounds (OCC) increase risk of cutaneous malignant melanoma (CMM). However, these studies have generally had no biologic measure of OCC exposure, and have been unable to control for sun exposure, the major known environmental risk factor for this disease. This preliminary study examined the relationship between OCC residues in plasma and risk of CMM adjusting for sun ... [Abstract] [Full-text] Multiple antimelanoma potential of dry olive leaf extract. Int J Cancer, 128(8): 1955-65. Various constituents of the olive tree (Olea europaea) have been traditionally used in the treatment of infection, inflammation, prevention of chronic diseases, cardiovascular disorders and cancer. The anticancer potential of dry olive leaf extract (DOLE) represents the net effect of multilevel interactions between different biologically active compounds from the extract, cancer cells and conventional therapy. In this context, it was of primary interest to evaluate the influence of DOLE on ... [Abstract] [Full-text] Plasma levels of polychlorinated biphenyls and risk of cutaneous malignant melanoma: a preliminary study. Int J Cancer, 128(8): 1872-80. A number of epidemiologic studies have suggested that exposure to polychlorinated biphenyls (PCB) and other organochlorine compounds (OCC) increase risk of cutaneous malignant melanoma (CMM). However, these studies have generally had no biologic measure of OCC exposure, and have been unable to control for sun exposure, the major known environmental risk factor for this disease. This preliminary study examined the relationship between OCC residues in plasma and risk of CMM adjusting for sun ... [Abstract] [Full-text] Articles on Melanoma published 21 February 2011: Melanoma-associated antigen genes - an update. Cancer Lett, 302(2): 85-90. To date, dozens of melanoma-associated antigens (MAGE) have been identified. Based on the differences in tissue-specific gene expression and gene structure, the MAGE family has been divided into two big subfamilies: MAGE-I and MAGE-II. MAGE-I genes were identified as a group of highly attractive targets for cancer immunotherapy because of their wide expression in a variety of malignant tumors but silent in normal adult cells except germ-line cells lacking human leukocyte antigen (HLA) ... [Abstract] [Full-text] © 2004-2011 Melanoma Research Today. All Rights Reserved. |
| ||||
