A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity.

Uterine leiomyomas (ULs), frequent benign tumours of the female reproductive tract, are associated with a range of symptoms and significant morbidity. Despite extensive research, there is no consensus on essential points of UL initiation and development. The main reason for this is a pronounced inter- and intratumoral heterogeneity resulting from diverse and complicated mechanisms underlying UL pathobiology. In this review, we comprehensively analyse risk and protective factors for UL development, UL cellular composition, hormonal and paracrine signalling, epigenetic regulation and genetic abnormalities. We conclude the need to carefully update the concept of UL genesis in light of the current data. Staying within the framework of the existing hypotheses, we introduce a possible timeline for UL development and the associated key events-from potential prerequisites to the beginning of UL formation and the onset of driver and passenger changes.

Molecular Clues to Understanding Causes of Human-Assisted Reproduction Treatment Failures and Possible Treatment Options.

More than forty years after the first birth following in vitro fertilization (IVF), the success rates of IVF and of IVF-derived assisted reproduction techniques (ART) still remain relatively low. Interindividual differences between infertile couples and the nature of the problems underlying their infertility appear to be underestimated nowadays. Consequently, the molecular basis of each couple's reproductive function and of its disturbances is needed to offer an individualized diagnostic and therapeutic approaches to each couple, instead of applying a standard or minimally adapted protocols to everybody. Interindividual differences include sperm and oocyte function and health status, early (preimplantation) embryonic development, the optimal window of uterine receptivity for the implanting embryo, the function of the corpus luteum as the main source of progesterone production during the first days of pregnancy, the timing of the subsequent luteoplacental shift in progesterone production, and aberrant reactions of the uterine immune cells to the implanting and recently implanted embryos. In this article, the molecular basis that underlies each of these abnormalities is reviewed and discussed, with the aim to design specific treatment options to be used for each of them.

[Corrigendum] Integrated transcriptomic and epigenetic data analysis identifies aberrant expression of genes in acute myeloid leukemia with MLL­AF9 translocation.

Following the publication of this paper, the authors have realized that the final article did not indicate in the Authors' Contribution section that Fangce Wang and Zheng Li made equal contributions to this work (FW and ZL performed most of the statistical analyses and drafted the initial version of the manuscript). Therefore, the affiliations for this paper should have been written as follows (changes are highlighted in bold): FANGCE WANG1*, ZHENG LI1*, GUANGMING WANG1, XIAOXUE TIAN1, JIE ZHOU1, WENLEI YU1, ZHUOYI FAN1, LIN DONG1, JINYUAN LU1, JUN XU2, WENJUN ZHANG1 and AIBIN LIANG1. 1Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200092; 2Medical Center for Stem Cell Engineering and Transformation, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China. *Contributed equally. The authors confirm that there are no further errors in the paper, and all the authors agree to this correction. The authors and the Editor apologize for any inconvenience caused. [the original article was published in Molecular Medicine Reports 21: 883­893, 2020, DOI: 10.3892/mmr.2019.10849].

Integrated transcriptomic and epigenetic data analysis identifiesaberrant expression of genes in acute myeloid leukemia with MLL­AF9 translocation.

Rearrangement of the mixed lineage leukemia (MLL; also known as lysine methyltransferase 2A) gene is a recurrent genomic aberration in acute myeloid leukemia (AML). MLLT3, super elongation complex subunit (AF9) is one of the most common MLL fusion partners in AML. The present study aimed to explore the aberrant expression of genes associated with the MLL­AF9 translocation and identified potential new targets for the therapy of AML with MLL­AF9 translocation. The transcriptomic and epigenetic datasets were downloaded from National Center of Biotechnology Information Gene Expression Omnibus (GEO) database. Differentially expressed genes were obtained from two independent datasets (GSE68643 and GSE73457). Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. MLL­AF9­associated chromatin immunoprecipitation sequencing (ChIP­Seq) data was analyzed and identified binding sites for MLL­AF9 and wild type MLL (MLL WT). The ChIP­Seq of histone modification data was downloaded from the GEO database, including histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 79 dimethylation (H3K79me2) and histone 3 lysine 27 acetylation (H3K27ac), was used for comparing histone modification marks between the MLL­AF9 leukemia cells and normal hematopoietic cells at MLL­AF9 and MLL WT binding sites. The differentially expressed genes with the same trend in H3K79me2, H3K27ac and H3K4me3 alteration were identified as potential MLL­AF9 direct target genes. Upon validation using RNA­Seq data from the Therapeutically Applicable Research to Generate Effective Treatments AML project, eight potential direct target genes of MLL­AF9 were identified and further confirmed in MLL­AF9 mouse model using reverse transcription­quantitative polymerase chain reaction. These genes may have a critical role in AML with MLL­AF9 translocation.

Role of GFI1 in Epigenetic Regulation of MDS and AML Pathogenesis: Mechanisms and Therapeutic Implications.

Growth factor independence 1 (GFI1) is a DNA binding zinc finger protein, which can mediate transcriptional repression mainly by recruiting histone-modifying enzymes to its target genes. GFI1 plays important roles in hematopoiesis, in particular by regulating both the function of hematopoietic stem- and precursor cells and differentiation along myeloid and lymphoid lineages. In recent years, a number of publications have provided evidence that GFI1 is involved in the pathogenesis of acute myeloid leukemia (AML), its proposed precursor, myelodysplastic syndrome (MDS), and possibly also in the progression from MDS to AML. For instance, expression levels of the GFI1 gene correlate with patient survival and treatment response in both AML and MDS and can influence disease progression and maintenance in experimental animal models. Also, a non-synonymous single nucleotide polymorphism (SNP) of GFI1, GFI1-36N, which encodes a variant GFI1 protein with a decreased efficiency to act as a transcriptional repressor, was found to be a prognostic factor for the development of AML and MDS. Both the GFI1-36N variant as well as reduced expression of the GFI1 gene lead to genome-wide epigenetic changes at sites where GFI1 occupies target gene promoters and enhancers. These epigenetic changes alter the response of leukemic cells to epigenetic drugs such as HDAC- or HAT inhibitors, indicating that GFI1 expression levels and genetic variants of GFI1 are of clinical relevance. Based on these and other findings, specific therapeutic approaches have been proposed to treat AML by targeting some of the epigenetic changes that occur as a consequence of GFI1 expression. Here, we will review the well-known role of Gfi1 as a transcription factor and describe the more recently discovered functions of GFI1 that are independent of DNA binding and how these might affect disease progression and the choice of epigenetic drugs for therapeutic regimens of AML and MDS.