1996;74:1518C1525
1996;74:1518C1525. of epigenetic drugs ML-281 for the treatment of hematological malignancies. DNMTs that are essential in the generation of new methylation patterns during embryogenesis and germ-cell development. Additionally, there is a class of methyl-CpG-binding proteins (MBDs) which bind to methyl-CpG within gene promoters and prevent the binding of specific transcription factors to their recognition sites [7, 8]. Another family of important mediators of DNA methylation is the Ten-Eleven-Translocation (TET) family, which includes proteins that utilize oxygen and -ketoglutarate (-KG) to catalyze different reactions, including the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). The TET family of proteins was first identified as a fusion partner of mixed-lineage leukemia (MLL) in patients with t(10;11)(q22;q23) acute myeloid leukemia (AML). Although the biological functions of 5-hmC are still largely unknown, recent evidence suggests that it may play a functional role in stem cell biology [8]. DNA methylation appears to be critically involved in hematopoietic cell differentiation and the development of hematological malignancies, since several genes that regulate the processing of 5-mC are commonly found to be mutated in hematopoietic tumors [9]. DNMTs DNMTs are essential for early stage of hematopoiesis. The absence of DNMT-1 in HSC impaired self-renewal were unable to suppress key myeloerythroid regulators and lost their ability to differentiate into lymphoid progeny, thus ML-281 demonstrating that DNA methylation is necessary to protect normal HSC from lineage restriction [10]. More recently, Challen GA et al. demonstrated that loss ML-281 progressively impairs the differentiation capacity of HSC and is accompanied by a simultaneous expansion of HSC in the bone marrow. Furthermore, DNMT3A activity might impair the differentiation potential of HSC, providing a possible explanation for how DNMT3A mutations can contribute to AML and myelodysplastic syndrome (MDS) pathogenesis. In fact, several studies using large-scale array-based genomic resequencing and whole-genome sequencing of human leukemia have revealed recurrent DNMT3A mutations at multiple sites in AML patients. Greater than 50% of DNMT3A mutations occur at a single amino acid position, R882, located within the catalytic domain; this leads to reduced enzymatic activity [12]. Consistently, the presence of DNMT3A gene mutations was detected in approximately 20% of patients with AML, a genetic change associated with a shorter overall survival [13]. However, DNMT3A mutations did not correlate with any variations in 5-mC content in AML genomes and were not associated with a specific methylation or gene expression signature in AML patients, so further evaluation is needed to better define the potential pathogenic role of these mutations [13, 14]. DNA hypermethylation Several lines of evidence point to a role for DNA hypermethylation in the molecular pathogenesis of hematological malignancies (for review see [15]). In fact, the gene encoding the cell cycle regulator p15/INK4b is frequently inactivated by promoter hypermethylation in a large proportion of leukemia patients. Aberrant DNA hypermethylation impairs p15 growth-suppressive properties, allowing leukemic cells to escape inhibitory signals in the bone marrow. Hypermethylation of p15 promoter happens in approximately 50% of individuals with chronic myeloid leukemia (CML), AML, and acute lymphoblastic leukemia (ALL) and represents a key feature of the malignant progression of MDS [16]. In fact, improved CpG methylation in the INK4b locus was associated with the progression of MDS to AML, therefore suggesting that aberrant p15 gene hypermethylation may be regarded as an early event in myeloid cell transformation [17]. A stringent association between aberrant promoter methylation and DNMT manifestation has been found in MDS, a hematological malignancy in which the list of genes inactivated by hypermethylation has grown substantially (for review observe [18]). Recently, using an MDS model, DNA hypermethylation of several genes involved in normal hematopoiesis was recognized and associated with elevated DNMT isoform manifestation, supporting the notion that.Genes Dev. and prevent the binding of specific transcription factors to their acknowledgement sites [7, 8]. Another family of important mediators of DNA methylation is the Ten-Eleven-Translocation (TET) family, which includes proteins that utilize oxygen and -ketoglutarate (-KG) to catalyze different reactions, including the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). The TET family of proteins was first identified as a fusion partner of mixed-lineage leukemia (MLL) in individuals with t(10;11)(q22;q23) acute myeloid leukemia (AML). Even though biological functions of 5-hmC are still largely unknown, recent evidence suggests that it may play a functional part in stem cell biology [8]. DNA methylation appears to be critically involved in hematopoietic cell differentiation and the development of hematological malignancies, since several genes that regulate the processing of 5-mC are commonly found to be mutated in hematopoietic tumors [9]. DNMTs DNMTs are essential for early stage of hematopoiesis. The absence of DNMT-1 in HSC impaired self-renewal were unable to suppress important myeloerythroid regulators and lost their ability to differentiate into lymphoid progeny, therefore demonstrating that DNA methylation is necessary to protect normal HSC from lineage restriction [10]. More recently, Challen GA et al. shown that loss gradually impairs the differentiation capacity of HSC and is accompanied by a simultaneous development of HSC in the bone marrow. Furthermore, DNMT3A activity might impair the differentiation potential of HSC, providing a possible explanation for how DNMT3A mutations can contribute to AML and myelodysplastic syndrome (MDS) pathogenesis. In fact, several studies using large-scale array-based genomic resequencing and whole-genome sequencing of human being leukemia have exposed recurrent DNMT3A mutations at multiple sites in AML individuals. Greater than 50% of DNMT3A mutations happen at a single amino acid position, R882, located within the catalytic website; this prospects to reduced enzymatic activity [12]. Consistently, the presence of DNMT3A gene mutations was recognized in approximately 20% of individuals with AML, a genetic change associated with a shorter overall survival [13]. However, DNMT3A mutations did not correlate with any variations in 5-mC content material in AML genomes and were not associated with a specific methylation or gene manifestation signature in AML individuals, so further evaluation is needed to better define the potential pathogenic role of these mutations [13, 14]. DNA hypermethylation Several lines of evidence point to a role for DNA hypermethylation in the molecular pathogenesis of hematological malignancies (for review observe [15]). In fact, the gene encoding the cell cycle regulator p15/INK4b is frequently inactivated by promoter hypermethylation in a large proportion of leukemia individuals. Aberrant DNA hypermethylation impairs p15 growth-suppressive properties, permitting leukemic cells to escape inhibitory signals in the bone marrow. Hypermethylation of p15 promoter happens in approximately 50% of individuals with chronic myeloid leukemia (CML), AML, and acute lymphoblastic leukemia (ALL) and represents a key feature of the malignant progression of MDS [16]. In fact, improved CpG methylation in the INK4b locus was associated with the progression of MDS to AML, therefore suggesting that aberrant p15 gene hypermethylation may be considered an early event in myeloid cell transformation [17]. A stringent association between aberrant promoter methylation and DNMT manifestation has been found in MDS, a hematological malignancy in which the list of genes inactivated by hypermethylation has grown substantially (for review observe [18]). Recently, using an MDS model, DNA hypermethylation of several genes involved in normal hematopoiesis was recognized and associated with elevated DNMT isoform manifestation, supporting the notion that this disease is characterized by common epigenetic deregulation [19]. DNA hypomethylation Loss of methylation has been reported in several hematological malignancies. Genome-wide DNA methylation takes place mainly at repeated sequences, including short and long interspersed nuclear elements and LTR elements, segmental duplications and centromeric and subtelomeric areas [20, 21]. The Long Interspersed Nucleotide Element-1 (Collection-1) repeated elements are the most well-documented interspersed repeated elements showing hypomethylation in various cancers, including ALL. Hypomethylation in the promoter region of Collection-1 can PROM1 lead to the reactivation of transposable Collection-1 elements that may cause chromosomal instability, as observed in CML [22]. TET enzymes and DNA hydroxymethylation Mutations in TET2 have been found in a range of hematological malignancies, including AML, MDS, myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML) with frequencies of 24%, 19%, 12% and 22%, respectively [23]. In a.