Journal of Experimental Hematology DNMT3A MDS PMF DNMT3A

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1 1556 Journal of Experimental Hematology Article ID DNMT3A DNA AML DNA 3A DNMT3A DNA 20% 882 DNMT3A 60 AML-M 4 M 5 MDS PMF DNMT3A DNMT3A MRD DNMT3A DNMT3A DNA R A DNMT3A Gene Mutations in Acute Myeloid Leukemia Review CHEN Ya-Mei LU Quan-Yi Department of Hematology Xiamen University Zhongshan Hospital Xiamen Fujian Province China Corresponding Author LU Quan-Yi Senior Physician Professor. Tel quanyilu@ hotmail. com Abstract Epigenetic changes including abnormal DNA methylation have been identified to play significant roles in tumor initiation and progression. Recently mutations of DNMT3A were identified in acute myeloid leukemia AML which possibly caused changes in DNA methylation and indicated a poor prognosis. Sequencing analysis showed that most of the mutations were single nucleotide variations including a hotspot Arg882. DNMT3A mutations were detected in about 20% AML patients and closely associated with the age over 60 the M 4 M 5 subtypes and intermediate-risk cytogenetics. Others showed that these alterations also present in myelodysplastic syndrome MDS and primary myelofibrosis PMF prior to development of the obvious leukemia indicating that these mutations might contribute to leukemogenesis. However its prognostic value of minimal residual disease and role of therapeutic targets are still unclear focusing on a large cohort of AML patients will solve these issues. In this review the achievement in studing DNMT3A gene mutation are summarized and the latest research progress is briefly discussed. Key words DNMT3A gene epigenetics DNA methylation acute myeloid leukemia J Exp Hematol acute myeloid leukemia AML NPM /10 FLT3 3 CEBPA 4 IDH ASXL1 DNMT3A 5 6 DNMT3A DNA 3ADNA AML WHO AML 40% quanyilu@ hotmail. com AML NC-AML

2 DNMT3A DNMT3A CpG DNA DNA DNMT DNA DNA CpG DNA RNA DNA DNA DNA DNA 5 5 DNMT3A - - CpG CpG DNMT 2010 Yamashita DNMT3A DNMT 2p % DNMT3A 882 DNA bp ORF bp DNA CDS bp % Ley 6 DNMT1 DNMT2 DNMT3B AML DNMT3A DNMT3L DNMT 22% % S- SAM 2 / 3 DNMT3A ' 4 8 DNMT3A 3B N R882H R882C R882P PHD α / R882S X ARTX Otani 9 DNMT3A Yan 16 H3K4 AML-M 5 DNMT3A 20. 5% - AML-M 4 DNMT N C % DNMT3A GK DNA DNA DNMT3A Walter 17 8% 12 /150 3B MDS 882 DNA CpG Abdel-Wahab 18 DNMT1 DNMT3 7% 3 /46 AML Qiao DNMT 11 AML % DNMT3A DNMT3A DNMT3A DNA CEBPA DNMT3A CD4 /CD7 DNA DNMT3A 13 DNA

3 1558 J Exp Hematol DNMT3A AML MDS Blum 27 DNMT3A DNA AML DNA DNMT3A mrna DNMT3A Ley 6 Yan 16 AML-M 4 AML-M 5 DNMT3A AML-M WHO t t 8 21 inv 16 1 DNMT3A AML DNMT3A 2 20% 882 HSC HSC DNA Ley NPM1 FLT3 DNMT3A DNA AML HSC DNMT3A DNMT3B Tadokoro 21 DNMT3A DNMT3B HSC HSC DNMT3A HSC 40% NC- DNMT3A AML NPM1 FLT3 CEBPA 1 DNMT3A NPM1 FLT3 CEBPA IDH1 IDH2 JAK2 Ley % NC-AML TET2 ASXL1 NPM1 CEBPA DNMT3A NC-AML DNMT3A Ley 6 MLL RARα DNMT3A DNMT3A Walter 17 Abdel- AML Wahab 18 DNMT3A 30% - 50% RNA mir-29b DNMT3A AML MRD DNMT3A DNMT Ley 6

4 DNMT3A 1559 DNMT3A HSC DNMT3A ASXL1 CBL IDH and IKZF1. Leukemia HSC 1138 myeloid leukemia. N Engl J Med DNMT3A AML AML PCR Carcinogenesis DNMT3A DNA DNMT3A PML- RARα RUNX1-RUNX1T1 CBFB-MYH11 Dnmt3 enzymes in embryonic development DNMT3A AML MRD HSC from an alternative promoter localizes to DNMT3A DNMT3A next generation. Reprod Fertil Dev Gregory TK Wald D Chen Y et al. Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics. J Hematol Oncol Verhaak RG Goudswaard CS van Putten W et al. Mutations in nucleophosmin NPM1 in acute myeloid leukemia AML association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms JAK2 MPL TET Ley TJ Ding L Walter MJ et al. dnmt3a mutations in acute Kanai Y Hirohashi S. Alterations of DNA methylation associated with abnormalities of DNA methyltransferases in human cancers during transition from a precancerous to a malignant state. 8 Hermann A Gowher H Jeltsch A. Biochemistry and biology of mammalian DNA methyltransferases. Cell Mol Life Sci Otani J Nankumo T Arita K et al. Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep Hu YG Hirasawa R Hu JL et al. Regulation of DNA methylation activity through Dnmt3L promoter methylation by Hum Mol Genet 11 Tang M Xu W Wang Q et al. Potential of DNMT and its Epigenetic Regulation for Lung Cancer Therapy. Curr Genomics 12 Chen T Ueda Y Xie S et al. A novel Dnmt3a isoform produced euchromatin and its expression correlates with active de novo methylation. J Biol Chem 13 Trasler JM. Gamete imprinting setting epigenetic patterns for the 14 Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics 15 Yamashita Y Yuan J Suetake I et al. Array-based genomic resequencing of human leukemia. Oncogene Yan XJ Xu J Gu ZH et al. Exome sequencing identifies somatic mutation of DNA methyltransferase gene dnmt3a in acute monocytic leukemia. Nat Genet Walter MJ Ding L Shen D et al. Recurrent dnmt3a mutations in patients with myelodysplastic syndromes. Leukemia Abdel-Wahab O Pardanani A Rampal R et al. DAMT3A mutational analysis in primary myelofibrosis chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms. Leukemia DNMT3a Kiyoi H Naoe T. Biology clinical relevance and molecularly targeted therapy in acute leukemia with FLT3 mutation. Int J Hematol Pabst T Mueller BU Zhang P et al. Dominant-negative mutations of CEBPA encoding CCAAT / enhan cer binding protein-alpha C /EBPalpha in acute myeloid leukemia. Nat Gene Ji H Ehrlich LI Seita J et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature Tadokoro Y Ema H Okano M et al. De nove DNA mrthyltransferase is essential for self-renewal but not for differentiation in hematopoietic stem cells. J Exp Med

5 1560 J Exp Hematol Miremadi A Oestergaard MZ Pharoah PDP et al. Cancer genetics of epigenetic genes. Hum Mol Genet Spec No 1 R28 - R49 23 Shervington A Patel R. Silencing DNA methyltransferase DNMT enhances glioma chemosensitivity. Oligonucleotides Chik F Szyf M. Effects of specific DNMT-gene depletion on cancer cell transformation and breast cancer cell invasion towards selective DNMT inhibitors. Carcinogenesis Cashen AF Schiller GJ O'Donnell MR et al. Multicenter phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol Fandy TE Herman JG Kerns P et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood Blum W Garzon R Klisovic RB et al. Clinical response and mir-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A Medina-Franco JL Caulfield T. Advances in the computational development of DNA methyltransferase inhibitors. Drug Discov Today Stintzing S Kemmerling R Kiesslich T et al. Myelodysplastic syndrome and histone deacetylase inhibitors " to be or not to be acetylated" J Biomed Biotechnol Epub 2011 May Huang Q Hu Q Li Q. Identification of 8 foodborne pathogens by multicolor combinational probe coding technology in a single realtime PCR. Clin Chem