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1Department Internal Medicine I, Division Hematology/Oncology, University of Freiburg Medical Center, Hugstetter Str., D 79106 Freiburg, GermanyTop of pageAbstractFrequent genetic alterations in hematopoietic neoplasias (chromosomal translocations, point mutations, etc.) have provided biologic targets for the development of effective novel therapies. A rapidly increasing body of knowledge provides evidence also for multiple epigenetic alterations in these disorders, which can complement or even precede genetic aberrations. the cyclin dependent kinase inhibitors p16, p15, p21) is frequently mediated by DNA methylation of gene promoters. The acetylation state of histones (functionally linked to the DNA methylation state by the methylcytosine binding protein 2, recruiting histone deacetylases) provides a second major epigenetic silencing mechanism. Therapeutic reversal strategies are being developed for acute leukemias, myelodysplastic syndromes and malignant lymphomas. Since the discovery of the DNA methyltransferase (Dnmt) inhibitory activity of two azanucleosides (5 azacytidine, 5 aza 2' deoxycytidine/decitabine) even at doses with minimal nonhematologic toxicity, both have been clinically studied in several myeloid neoplasias, particularly in elderly patients unable to tolerate aggressive treatment. Further development of agents counteracting aberrant methylation is directed at more targeted approaches, for example, antisense molecules against Dnmts. Histone deacetylases (HDACs) can be inhibited by numerous compounds (sodium phenylbutyrate, valproic acid, novel compounds such as depsipeptide), which have entered the clinical arena in similar indications as Dnmt inhibitors. Impressive effects of HDAC inhibition in acute promyelocytic leukemia models (PML/RARA expression) translate the finding of HDAC recruitment by this chimeric transcription factor to its target genes. The recent discovery of recruitment by PML/RARA also of Dnmt activity to the retinoic acid receptor beta promoter makes it an interesting candidate for Dnmt inhibitors. Studies combining a 're expressor' strategy with inhibitors of Dnmts and HDACs are underway. 5 Methylcytosine differs from cytosine by addition of a methyl group at the C5 position of the pyrimidine ring when present in a CpG dinucleotide (Figure 1). The transfer of methyl groups from S adenosyl L methionine (SAM) to cytosine is a heritable mechanism that is catalysed by several DNA methyltransferases (DNMTs) during cell replication. At least three different DNMTs are involved in cellular DNA methylation: DNMT1, DNMT3A, DNMT3B and splicing variants (Singal and Ginder, 1999; Robertson and Wolffe, 2000). In somatic cells, DNMT1 shows highest activity and affinity to hemimethylated DNA, being mainly responsible for maintaining methylation patterns during replication ('maintenance methyltransferase'). DNMT3A and 3B are equally effective in methylation of hemimethylated and unmethylated DNA, and they are required for de novo methylation (Okano et al., 1999). 5 Methylcytosine differs from cytosine by the addition of a methyl group at position 5 of the pyrimidine ring. The DNA demethylating effects of the 5 aza analogues are associated with the substitution of C5 by N. R, ribose; dR, deoxyribose
In hematopoietic neoplasias, large numbers of genes have been studied for methylation changes compared to their untransformed cellular counterparts. These have been recently reviewed by Chim et al. (2002), and the results are summarized in Table 1. Investigations have focused on genes involved in cell cycle regulation (several of them proven or bona fide tumor suppressor genes), genes involved in growth, differentiation and signalling, metastasis and other functions appearing as reasonable candidates during neoplastic transformation. A certain lineage specificity of the genes being inactivated by methylation is apparent: p15 is frequently hypermethylated in myeloid neoplasias and acute lymphoid leukemia, whereas p16, which is only rarely involved in myeloid neoplasms, is frequently methylated in non Hodgkin's lymphoma (Drexler, 1998). A different mechanism of promoter methylation was demonstrated in the leukemia model of acute promyelocytic leukemia (APL) expressing the chimeric transcription factor PML/RAR (Di Croce et al., 2002). It was shown that PML/RAR was able to mediate silencing by DNA methylation of the target gene RAR, via recruitment of DNMT3a. Treatment of cells with retinoic acid induced demethylation of this promoter, with gene re expression and reversion of the malignant phenotype by differentiation. By these results, a mechanistic link between genetic changes in leukemia and epigenetic modification during transformation was first demonstrated. Hypermethylation thus contributed to early steps in leukemogenesis, at least in this subtype of leukemia, prompting similar analyses also in other leukemias bearing oncogenic transcription factors.
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Mumbai, March 05, 2008At the 134th Governing Council Meeting of the Indo French Chamber of Commerce Industry (IFCCI) held in Mumbai. Mr. Uday Khanna, CEO of Lafarge India Private Limited was appointed President of the bilateral Chamber that holds responsibility for enhancing business relations between France and India.Established on 3rd February 1977 in Mumbai, India, the IFCCI has been in existence for over quarter of a century. It is a bilateral business organization and whose 600 odd members are French and Indian companies from various sectors of activity.Present in over 70 countries, Lafarge is the world leader in building materials, with top ranking positions in all of its businesses: Cement, Aggregates Concrete and Gypsum. Lafarge is the only company in the construction materials sector to be listed in the 2007 100 Global Most Sustainable Corporations in the World .Mr. Uday Khanna, CEO, Lafarge India, joined Lafarge in Paris on 1st June 2003 as Senior Vice President in Group Strategy. Mr. Khanna, a Chartered Accountant, was associated with Hindustan Lever / Unilever for almost 30 years in a variety of Financial, Commercial and General Management roles both nationally and internationally.Mr. Trilochan Singh SAHNEY, Chairman and Managing Director, NRB Bearings Ltd. and Mr. Xavier BERTRAND, Managing Director, Chanel India Pvt. Ltd. continue as the Vice President of the Chamber. Mr. Jean Luc FERRANT has been appointed as the Director General and Country Head of the IFCCI. Banyan Netfaqs Pvt Ltd takes no responsibility for and disclaims the information available in form of press releases across our network.
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