DHODH modulates transcriptional elongation in the neural crest and melanoma

Stem Cell Program and Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 42.35). 03/2011; 471(7339):518-22. DOI: 10.1038/nature09882
Source: PubMed

ABSTRACT 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.

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Available from: Matthew L Tomlinson, Aug 27, 2015
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    • "Miller syndrome or postaxial acrofacial dysostosis (MIM 263750), characterised by both craniofacial and limb anomalies, is another example of a clinically recognisable acrofacial dysostosis in which recessive mutations in DHODH result in reduced de novo pyrimidine synthesis [Rainger et al., 2012]. Interestingly, inhibition of DHODH in zebrafish embryos leads to complete abrogation of neural crest development similar to Treacle [White et al., 2011]. The involvement of PHAX in PRS with or without CCA merits further work particularly in the absence of any human cases with intragenic mutations. "
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    ABSTRACT: Pierre Robin sequence (PRS) is an etiologically distinct subgroup of cleft palate. We aimed to define the critical genomic interval from five different 5q22-5q31 deletions associated with PRS or PRS-associated features and assess each gene within the region as a candidate for the PRS component of the phenotype. Clinical array-based comparative genome hybridisation (aCGH) data were used to define a 2.08 Mb minimum region of overlap among four de novo deletions and one mother-son inherited deletion associated with at least one component of PRS. Commonly associated anomalies were talipes equinovarus (TEV), finger contractures and crumpled ear helices. Expression analysis of the orthologous genes within the PRS critical region in embryonic mice showed that the strongest candidate genes were FBN2 and PHAX. Targeted aCGH of the critical region and sequencing of these genes in a cohort of 25 PRS patients revealed no plausible disease-causing mutations. In conclusion, deletion of ∼2 Mb on 5q23 region causes a clinically recognisable subtype of PRS. Haploinsufficiency for FBN2 accounts for the digital and auricular features. A possible critical region for TEV is distinct and telomeric to the PRS region. The molecular basis of PRS in these cases remains undetermined but haploinsufficiency for PHAX is a plausible mechanism.
    European Journal of Medical Genetics 10/2014; 57(10). DOI:10.1016/j.ejmg.2014.08.007 · 1.49 Impact Factor
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    • "White et al. [14] reported that leflunomide inhibits transcriptional elongation of the genes involved in self-renewal of neural progenitor cells through inhibition of DHO-DHase activity. These investigators further demonstrated that leflunomide at low doses cooperates with PLX4720, a B-Raf kinase inhibitor, to effectively inhibit melanoma cell proliferation and tumor growth [14]. Our early studies using a lymphadenopathy and autoimmune disease model in MRL/MpJ-lpr/lpr mice and a tumor xenograft model demonstrated that the immunosuppressive and antitumor activities of leflunomide are largely independent of the pyrimidine nucleotide synthesis pathway [4] [5] since uridine co-administration with leflunomide normalized pyrimidine nucleotide levels in tumor tissues but did not antagonize the antitumor activity of leflunomide in two xenograft models [5]. "
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    Neoplasia (New York, N.Y.) 10/2014; 16(10):824–834. DOI:10.1016/j.neo.2014.08.006 · 5.40 Impact Factor
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    • "Therefore, GSNOR inhibitors emerge as highly specific drug candidates to provide enhanced hepatoprotection without systemic side effects. To date, chemical screens in zebrafish have led to clinical trials in blood stem cell therapy (Goessling et al., 2011; North et al., 2007) and melanoma (White et al., 2011). Here, we reveal a possible clinical application of GSNOR inhibitors in regenerative medicine with the potential to extend to other causes of liver failure and injury of other organs. "
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