132 Partial tandem duplication (PTD) of MLL have been detected in AML with trisomy 11 and
in 5-11% of CN-AML. 41 It has been suggested that MLL-PTD may contribute to AML development through DNA hypermethylation and epigenetic silencing of tumor suppressor genes. 134 The clinical significance of MLL-PTD in CN-AML patients remains controversial, having been associated with inferior outcome or no prognostic impact www.selleckchem.com/HSP-90.html (in cases treated with four cycles of consolidation or autologous HSCT). 41 The features of other mutations that have been detected at variable frequency in CN-AML are briefly summarized below. These mutations are detectable in 10-13% of CN-AML.[135], [136] and [137] Their clinical significance is uncertain, having been associated with inferior outcome[135] and [136] or no prognostic impact.137 Differences in post-remission therapy may account for these
conflicting results. Mutations usually cluster in the Runt domain of the gene. They have been found in association with undifferentiated AML (M0 FAB) and with trisomies 13 and 21.138 In two studies, frequencies of RUNX1 mutations within CN-AML were quite different, ranging from 6.3% 139 to 26.3%. 138 In general, RUNX1 mutations seem to predict an inferior outcome. [138], [139] and [140] Mutations of the BCOR GPCR Compound Library in vitro (BCL6 corepressor) gene were discovered by whole exome sequencing of a single Prostatic acid phosphatase CN-AML patient that was selected for analysis because of the absence of any known mutation. 129BCOR mutations occurred in about 4% of all CN-AML but were enriched in the subgroup of CN-AML without any known mutation (about 17% of cases). 129BCOR mutations may act by interfering with epigenetic mechanisms. 141DNMT3A mutations frequently associate with BCOR mutations. 129BCOR mutations seem to predict a poorer prognosis 129 but, given their rarity, confirmatory studies are needed. In spite of the great advances in the molecular characterization of CN-AML, there are still a number of issues that need to be addressed. Next generation sequencing (NGS) studies have revealed that AML (as well as other tumors) usually harbor hundreds of
mutated genes. However, most of them represent background mutations (which do not provide a selective advantage) and only a limited number are driver mutations (i.e. causing the tumor). Looking at recurrence is accepted as one the most important criteria for distinguishing the passenger from the driver mutations. The mutational frequencies of the driver genes so far identified in AML range from a few percent to more than 30%. In the near future, NGS studies of additional AML genomes will lead to the identification of new mutations in AML but it is unlikely (given the high number of genomes already sequenced) that the list of the most frequently recurrent mutations (e.g. those affecting NPM1, FLT3 and DNMT3A) will be drammatically changed.
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