Acute myeloid leukemia aml is a heterogeneous clonal disorder of myeloid precursors and the most common acute leukemia diagnosed in adults. The likely mechanism by which dnmt3a loss contributes to leukemogenesis is altered dna methylation and the attendant gene expression changes. Pdf characteristics of dnmt3a mutations in acute myeloid leukemia. Dnmt3a is a critical epigenetic modifier and tumor suppressor in the hematopoietic system.
Nov 10, 2010 dnmt3a mutations in acute myeloid leukemia 10. We recently reported the dna sequence and analysis of the genomes of two patients with acute myeloid leukemia aml with a normal karyotype. All mutations that are shown were confirmed to be somatic. Mutations in tet2 and dnmt3a genes are associated with. In this study, we decided to investigate dnmt3a possible expression changes with regard to their.
Likewise, none of the 11 patients with structural variations involving 11q23, the location of the mixedlineage leukemia gene, had dnmt3a mutations. Dnmt3a and poor prognoses among acute myeloid leukemia aml patients. Dnmt3a r882 mutation features and prognostic effect in. Mutations in the dnmt3a dna methyltransferase in acute.
A mutational and expressional analysis of dnmt3a in acute. Dnmt3a mutations represent a potential target in the pathogenesis of aml. Acute myeloid leukemia aml is a complex disease caused by mutations, deregulated gene expression, and epigenetic modifications of genes leading to increased proliferation and decreased differentiation. Acute myeloid leukemia with biallelic cebpa gene mutations and normal karyotype. Acute myeloid leukemia with biallelic cebpa gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. Pdf dnmt3a mutations in patients with acute myeloid.
Acute myeloid leukemia aml is a complex and heterogeneous hematopoietic neoplasm. Mutation in dnmt3a, which is highly recurrent in aml, causes major dysregulation of gene expression leading to upregulation of stemness genes and increased repopulation and selfrenewal of normal hsc ley et al. Other types of mutations such as truncations, insertions, or singlenucleotide. New studies reveal that 20% of individuals with acute myeloid leukemia harbor somatic mutations in dnmt3a encoding dna methyltransferase 3a. Genetic and epigenetic changes have been established in the pathogenesis of acute myeloid leukemia aml. Detection of highfrequency and novel dnmt3a mutations in. There are a number of reasons for this, but key among them is the considerable heterogeneity of this disease and the paucity of molecular markers that can be used to predict clinical outcomes and responsiveness to different therapies. Dnmt3a mutations are associated with poor prognosis in acute myeloid leukemia aml, but the stability of this mutation during the clinical course re. Frequency of different dnmt3acd mutations occurred in acute myeloid leukemia aml based on the research from oncokb precision oncology knowledge base, cbioportal the.
The new england journal of medicine n engl j med 363. Somatic mutations of dnmt3a occur in about 20% of acute myeloid leukemia aml patients. Studies indicate that patients with dnmt3a mutations suffer particularly poor prognoses, indicating novel therapies are needed. Quantitative detection of dnmt3a r882h mutation in acute. Background the impact of the allelic burden of asxl1, dnmt3a, jak2, tet2, and tp53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia aml. We examined 79 acute myeloid leukemia aml patients for dna methylation of 12 tumor suppressor genes tsg and 24 homeobox domain hox genes, and additionally for mutations in dnmt3a gene. Shown are data from samples banked at washington university that were obtained from 188 patients with aml. Acute myeloid leukemia aml is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood. This gene is frequently mutated in hematopoietic malignancies, including acute myeloid leukemia aml, with dnmt3a r878h being the most common mutant. Emerging evidence has linked the presence of dnmt3a and idh12 mutations with clinical outcomes, particularly in cytogenetically normal aml, and it is likely that this will have a significant impact on risk stratification in the future. Mutations were tested using polymerase chain reaction pcr for detecting flt3itd and allelespecific pcr to detect dnmt3a and npm1a mutations.
Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. Relationship between dnmt3a mutations and other common mutations in 188 patients with acute myeloid leukemia aml. Investigation of screening method for dnmt3a mutations by. Shown is the mutation status of each of 188 patients with aml on the basis of. What is the clinical implication of dnmt3a mutations in. Dnmt3a mutations might be associated with poorer prognosis, and is frequently associated with npm1 and flt3 mutations 34, 50, 5658. There are evidence that dnmt3a mutation are present in the early preleukemic cells. Clinical effect of combined mutations in dnmt3a, flt3itd. What is the clinical implication of dnmt3a mutations in acute. Dna methyltransferase 3a dnmt3a gene mutations have been. Therapeutic targeting of preleukemia cells in a mouse.
Acute myeloid leukemia aml is an attractive system for investigating the effect of preventative treatment because this disease is often preceded by a premalignant state clonal hematopoiesis or. Dnmt3a mutations occur in approximately 20% of aml cases and are associated with changes in dna methylation. Pdf dnmt3a mutations in acute myeloid leukemia michael. Functional analysis of dnmt3a dna methyltransferase. Tet2 mutations improve the new european leukemianet risk classification of acute myeloid leukemia. Dnmt3a mutations are associated with poor prognosis in acute myeloid leukemia aml, but the stability of this mutation during the clinical course remains unclear. Impact of the variant allele frequency of asxl1, dnmt3a. The acute myeloid leukemia variant dnmt3a arg882his is a dnmt3blike enzyme biorxiv 2019 0. Dnmt3a mutations in acute myeloid leukemia request pdf. Dot1l as a therapeutic target for the treatment of dnmt3a. Dna methyltransferase 3a dnmt3a is one of the commonly mutated genes in acute myelogenous leukemia. Aml is the most common leukemia among adults, and the incidence is increasing with aging 1 3.
Acute myeloid leukemia aml is a heterogeneous disease associated with various genetic abnormalities. Dnmt3a mutations in acute myeloid leukemia new england. Decreased dna methylation in acute myeloid leukemia. Mutations in dna methyltransferase 3a dnmt3a are common in acute myeloid leukemia and portend a poor prognosis. Impact of the variant allele frequency of asxl1, dnmt3a, jak2. Dec 16, 2010 wholegenome sequencing is an unbiased approach for discovering somatic variations in cancer genomes. Functional analysis of dnmt3a dna methyltransferase mutations. Conditional knockin of dnmt3a r878h initiates acute myeloid. Acute myeloid leukemia aml is a complex and heterogeneous hematopoietic tissue neoplasm. Several molecular markers have been described that help to classify aml patients into risk groups. They mostly consist in heterozygous missense mutations targeting a hotspot site at r882 codon, which exhibit a dominant negative effect and are associated with high myeloblast count, advanced age, and poor prognosis. Although these leukemias have some gene expression. This gene is frequently mutated in hematopoietic malignancies, including acute myeloid leukemia aml, with.
Eukaryotic dna methylation prevents genomic instability by regulating the expression of oncogenes and tumorsuppressor genes. Incidence and prognostic influence of dnmt3a mutations in. They mostly consist in heterozygous missense mutations targeting a hotspot site at r882 codon, which. Nucleophosmin npm1 mutant acute myeloid leukemia aml is one of the most common types of aml. Dnmt3a mutations were positively associated with older age, higher. They mostly consist in heterozygous missense mutations targeting a. Despite its high prevalence, the mechanism of leukemogenesis is still. Dnmt3a mutations were significantly enriched in 56 of 166 patients with a cytogenetic profile associated with intermediate risk 33. Flt3 and dnmt3a mutations had significant negative. Mutations in the dnmt3a dna methyltransferase in acute myeloid. Dnmt3a mutations in patients with acute myeloid leukemia. Dnmt3a mutations represent one of the most frequent gene alterations detectable in acute myeloid leukemia aml with normal karyotype.
Using massively parallel dna sequencing, we identified a somatic mutation in dnmt3a, encoding a dna methyltransferase, in the genome of cells from a patient with aml with a normal karyotype. The origin and evolution of mutations in acute myeloid. Cytogenetically normal acute myeloid leukemia cnaml represents nearly 50% of human aml. We recently reported the dna sequence and analysis of the genomes of two patients. Cancer therapeutic targeting of preleukemia cells in a. Incidence and prognostic impact of dnmt3a and idh12 mutations in aml. Gene mutations of acute myeloid leukemia in the genome era. Dnmt3a and idh mutations in acute myeloid leukemia and. Different studies have shown a negative impact of dnmt3a mutations on outcomes in patients with aml. Clinical effect of combined mutations in dnmt3a, flt3itd, and npm1 among egyptian acute myeloid leukemia patients mosaad m. The average overall survival of acute myeloid leukemia patients with dnmt3a mutations was only 4 months.
Other highly recurrent mutations in genes such as idh1idh2. In addition, we showed that mutations in dnmt3a and tet2 may cause irregular dna. Currently, mutations of genes involved in regulation of epigenetic processes such as dnmt3a, tet2, ezh2, asxl1, idh12 etc. Dnmt3a mutations in patients with acute myeloid leukemia in. Npm1 and flt3 and cebpa mutations are common genomic alterations that play a crucial role in the.
Inhibition of dot1l reverses mutant dnmt3a induced gene expression, indicating a potential therapeutic strategy for amls harboring this mutation. Somatically acquired mutations in dnmt3a are causally associated with acute myeloid leukemia aml, and p. Role of dnmt3a, tet2, and idh12 mutations in preleukemic. Dnmt3a mutations in acute myeloid leukemia europe pmc. Epigenetic perturbations by arg882mutated dnmt3a potentiate. Radich6 abstract dnmt3a, flt3itd, and npm1a gene mutations, important determinants of outcome in acute. Keywords leukemia stem cells acute myeloid leukemia epigenetics dnmt3a tet2 idh introduction. Dnmt3a mutations in acute myeloid leukemia nature genetics. We demonstrate that mice with flt3 internal tandem duplication flt3 itd and inducible deletion of dnmt3a spontaneously develop a rapidly. The impact of the allelic burden of asxl1, dnmt3a, jak2, tet2, and tp53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia aml methods. Several different lossoffunction mutations have been found in all exons of dnmt3a, while a missense point mutation at amino acid r882 which decreases catalytic activity and dna binding. Jan 31, 2020, dnmt3a mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Microabstractdnmt3a, flt3itd, and npm1a gene mutations, important determinants of outcome in acute myeloid leukemia, were detected in 17.
Although the main cause of the disease is still unknown, some risk factors have been identified, including mutations in dnmt3a gene 14. Mutations in epigenetic modifiers were reported in patients with acute myeloid leukaemia aml including mutations in dna methyltransferase 3a gene dnmt3a in 20%30% patients and. Identification of two dnmt3a mutations compromising. Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. Here, we investigate the functional role of the missense mutations s714c, r635w, r736h, r771l, p777r, and f752v found in the catalytic domain of dnmt3a in aml patients.
Acute myeloid leukemia aml is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cells. In addition, we showed that mutations in dnmt3a and tet2 may cause irregular dna methylation patterns and transcriptional expression levels in 16 genes known to be involved in acute myeloid leukemia pathogenesis. Acute myeloid leukemia aml is a complex disease caused by mutations, deregulated gene expression, and epigenetic modifications of genes leading to increased proliferation and decreased differentiation of hematopoietic progenitor cells. We recently reported the dna sequence and analysis of the genomes of two patients with. Shown is the mutation status of each of 188 patients with aml on the basis. Dnmt3a and idh mutations in acute myeloid leukemia and other. Dna from 104 acute myeloid leukemia patients was tested for mutations in 12 exons encoding 3 major functional domains of dnmt3a. The influence of dnmt3a r882 mutations on adult acute myeloid leukemia aml prognosis is still controversial presently. Conditional knockin of dnmt3a r878h initiates acute.
Identification of two dnmt3a mutations compromising protein. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Therapeutic targeting of preleukemia cells in a mouse model. Wholegenome sequencing is an unbiased approach for discovering somatic variations in cancer genomes. Dec 18, 2019 frequency of different dnmt3a cd mutations occurred in acute myeloid leukemia aml based on the research from oncokb precision oncology knowledge base, cbioportal the cbioportal for cancer genomics, tcga the cancer genome atlas, and cosmic catalogue of somatic mutations in cancer databases and 12,19,20,21,22,23,24,25,26,27. Dnmt3a mutational status affects the results of doseescalated. Influence of dnmt3a r882 mutations on aml prognosis. Npm1 and flt3 and cebpa mutations are common genomic alterations that play a crucial role in the pathogenesis and evolution of the disease, particularly in the absence of amlassociated recurrent cytogenetic abnormalities. Dnmt3a mutations in 188 patients with acute myeloid leukemia aml. Dnmt3a mutations in acute myeloid leukemia article pdf available in new england journal of medicine 36325. Mar 29, 2011 new studies reveal that 20% of individuals with acute myeloid leukemia harbor somatic mutations in dnmt3a encoding dna methyltransferase 3a. The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia aml are unknown.
By using a conditional knockin approach, this study shows that dnmt3a r878h is sufficient to initiate. Prognostic effect is known to depend on certain biological factors as well as a combination of. Comparative examination of various pcrbased methods for. Decreased dna methylation in acute myeloid leukemia patients. The development of effective treatment strategies for most forms of acute myeloid leukemia aml has languished for the past several decades. Patients with dnmt3a mutations were older, had higher wbc and platelet counts, more often had a normal karyotype and mutations in npm1, flt3, and idh1 genes.
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