Document Detail


Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia.
MedLine Citation:
PMID:  23135354     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Gene mutations were found in acute myeloid leukemia (AML) and their importance has been noted. To clarify the importance and stability of mutations, we examined gene mutations in paired samples at diagnosis and relapse of 34 adult AML patients. Five acquired gene mutations were detected at relapse. Of the 45 gene mutations at diagnosis, 11 of them were lost at relapse. The acquired mutations at relapse were all class I mutations as Fms-like tyrosine kinase 3 (FLT3) and rat sarcoma viral oncogene homolog (RAS) mutations. The disappeared mutations at relapse were 3 of 11 internal tandem duplications of FLT3 (FLT3-ITD) (27.3%), 3 of 3 FLT3 tyrosine kinase domain (FLT3-TKD) (100%), 3 of 13 Nucleophosmin 1 (23.1%) and 2 of 5 CCAAT/enhancer-binding protein-α (40%) mutations. However, epigenetics-modifying gene (DNMT3a, TET2 and IDH1/2) mutations had no change between diagnosis and relapse samples, and may become minimal residual disease marker. The frequency of FLT3-ITD at relapse in patients with DNMT3a mutation at diagnosis is significantly higher than those in patients without them (P=0.001). Moreover, the high frequency of FLT3-ITD at relapse is also seen in AML cases that initially present with any epigenetics-modifying gene mutations (P<0.001). Our results indicate that epigenetics-modifying gene mutations may cause genetic instability and induce FLT3-ITD, leading to resistance to therapy and relapse.
Authors:
S Wakita; H Yamaguchi; I Omori; K Terada; T Ueda; E Manabe; S Kurosawa; S Iida; T Ibaraki; Y Sato; T Todoroki; T Hirakawa; T Ryotokuji; K Arai; T Kitano; Y Mitamura; F Kosaka; K Dan; K Inokuchi
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Publication Detail:
Type:  Journal Article     Date:  2012-11-08
Journal Detail:
Title:  Leukemia     Volume:  27     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-05-08     Completed Date:  2013-07-19     Revised Date:  2013-09-26    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1044-52     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, Division of Hematology, Nippon Medical School, Tokyo, Japan.
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MeSH Terms
Descriptor/Qualifier:
DNA (Cytosine-5-)-Methyltransferase / genetics*
DNA-Binding Proteins / genetics*
Epigenomics
Humans
Isocitrate Dehydrogenase / genetics*
Leukemia, Myeloid, Acute / genetics*
Mutation*
Proto-Oncogene Proteins / genetics*
Recurrence
fms-Like Tyrosine Kinase 3 / genetics*
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Proto-Oncogene Proteins; 0/TET2 protein, human; EC 1.1.1.41/Isocitrate Dehydrogenase; EC 1.1.1.41/isocitrate dehydrogenase 2, human; EC 1.1.1.42./IDH1 protein, human; EC 2.1.1.37/DNA (Cytosine-5-)-Methyltransferase; EC 2.1.1.37/DNA methyltransferase 3A; EC 2.7.10.1/FLT3 protein, human; EC 2.7.10.1/fms-Like Tyrosine Kinase 3
Comments/Corrections
Comment In:
Leukemia. 2013 Aug;27(8):1777-8   [PMID:  23417030 ]

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