DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies
Identifieur interne : 001642 ( Pmc/Corpus ); précédent : 001641; suivant : 001643DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies
Auteurs : Ap Im ; Ar Sehgal ; Mp Carroll ; Bd Smith ; A. Tefferi ; De Johnson ; M. BoyiadzisSource :
- Leukemia [ 0887-6924 ] ; 2014.
Abstract
The development of effective treatment strategies for most forms of acute myeloid leukemia (AML) has languished for the past several decades. 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. The recent large-scale sequencing of AML genomes is now providing opportunities for patient stratification and personalized approaches to treatment that are based on individual mutational profiles. It is particularly notable that studies by The Cancer Genome Atlas and others have determined that 44% of patients with AML exhibit mutations in genes that regulate methylation of genomic DNA. In particular, frequent mutation has been observed in the genes encoding DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), as well as Tet oncogene family member 2. This review will summarize the incidence of these mutations, their impact on biochemical functions including epigenetic modification of genomic DNA and their potential usefulness as prognostic indicators. Importantly, the presence of
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DOI: 10.1038/leu.2014.124
PubMed: 24699305
PubMed Central: 4234093
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mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies</title>
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<author><name sortKey="Johnson, De" sort="Johnson, De" uniqKey="Johnson D" first="De" last="Johnson">De Johnson</name>
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<author><name sortKey="Boyiadzis, M" sort="Boyiadzis, M" uniqKey="Boyiadzis M" first="M" last="Boyiadzis">M. Boyiadzis</name>
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mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies</title>
<author><name sortKey="Im, Ap" sort="Im, Ap" uniqKey="Im A" first="Ap" last="Im">Ap Im</name>
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<author><name sortKey="Sehgal, Ar" sort="Sehgal, Ar" uniqKey="Sehgal A" first="Ar" last="Sehgal">Ar Sehgal</name>
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<author><name sortKey="Carroll, Mp" sort="Carroll, Mp" uniqKey="Carroll M" first="Mp" last="Carroll">Mp Carroll</name>
<affiliation><nlm:aff id="A2">Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff>
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<author><name sortKey="Smith, Bd" sort="Smith, Bd" uniqKey="Smith B" first="Bd" last="Smith">Bd Smith</name>
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<author><name sortKey="Tefferi, A" sort="Tefferi, A" uniqKey="Tefferi A" first="A" last="Tefferi">A. Tefferi</name>
<affiliation><nlm:aff id="A4">Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA</nlm:aff>
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<author><name sortKey="Johnson, De" sort="Johnson, De" uniqKey="Johnson D" first="De" last="Johnson">De Johnson</name>
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<author><name sortKey="Boyiadzis, M" sort="Boyiadzis, M" uniqKey="Boyiadzis M" first="M" last="Boyiadzis">M. Boyiadzis</name>
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<series><title level="j">Leukemia</title>
<idno type="ISSN">0887-6924</idno>
<idno type="eISSN">1476-5551</idno>
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<front><div type="abstract" xml:lang="en"><p id="P1">The development of effective treatment strategies for most forms of acute myeloid leukemia (AML) has languished for the past several decades. 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. The recent large-scale sequencing of AML genomes is now providing opportunities for patient stratification and personalized approaches to treatment that are based on individual mutational profiles. It is particularly notable that studies by The Cancer Genome Atlas and others have determined that 44% of patients with AML exhibit mutations in genes that regulate methylation of genomic DNA. In particular, frequent mutation has been observed in the genes encoding DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), as well as Tet oncogene family member 2. This review will summarize the incidence of these mutations, their impact on biochemical functions including epigenetic modification of genomic DNA and their potential usefulness as prognostic indicators. Importantly, the presence of <italic>DNMT3A</italic>
, <italic>IDH1</italic>
or <italic>IDH2</italic>
mutations may confer sensitivity to novel therapeutic approaches, including the use of demethylating agents. Therefore, the clinical experience with decitabine and azacitidine in the treatment of patients harboring these mutations will be reviewed. Overall, we propose that understanding the role of these mutations in AML biology will lead to more rational therapeutic approaches targeting molecularly defined subtypes of the disease.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">8704895</journal-id>
<journal-id journal-id-type="pubmed-jr-id">5536</journal-id>
<journal-id journal-id-type="nlm-ta">Leukemia</journal-id>
<journal-id journal-id-type="iso-abbrev">Leukemia</journal-id>
<journal-title-group><journal-title>Leukemia</journal-title>
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<issn pub-type="ppub">0887-6924</issn>
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<article-id pub-id-type="doi">10.1038/leu.2014.124</article-id>
<article-id pub-id-type="manuscript">NIHMS632983</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title><italic>DNMT3A</italic>
and <italic>IDH</italic>
mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Im</surname>
<given-names>AP</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sehgal</surname>
<given-names>AR</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Carroll</surname>
<given-names>MP</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Smith</surname>
<given-names>BD</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tefferi</surname>
<given-names>A</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Johnson</surname>
<given-names>DE</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Boyiadzis</surname>
<given-names>M</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
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</contrib-group>
<aff id="A1"><label>1</label>
Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA</aff>
<aff id="A2"><label>2</label>
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA</aff>
<aff id="A3"><label>3</label>
The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology at the Johns Hopkins University, Baltimore, MD, USA</aff>
<aff id="A4"><label>4</label>
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA</aff>
<author-notes><corresp id="FN1">Correspondence: Dr AP Im, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Cancer Pavilion 5th floor, Pittsburgh, PA 15232, USA. <email>imap@upmc.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>3</day>
<month>10</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>04</day>
<month>4</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="ppub"><month>9</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>17</day>
<month>11</month>
<year>2014</year>
</pub-date>
<volume>28</volume>
<issue>9</issue>
<fpage>1774</fpage>
<lpage>1783</lpage>
<pmc-comment>elocation-id from pubmed: 10.1038/leu.2014.124</pmc-comment>
<permissions><copyright-statement>© 2014 Macmillan Publishers Limited All rights reserved</copyright-statement>
<copyright-year>2014</copyright-year>
</permissions>
<abstract><p id="P1">The development of effective treatment strategies for most forms of acute myeloid leukemia (AML) has languished for the past several decades. 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. The recent large-scale sequencing of AML genomes is now providing opportunities for patient stratification and personalized approaches to treatment that are based on individual mutational profiles. It is particularly notable that studies by The Cancer Genome Atlas and others have determined that 44% of patients with AML exhibit mutations in genes that regulate methylation of genomic DNA. In particular, frequent mutation has been observed in the genes encoding DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), as well as Tet oncogene family member 2. This review will summarize the incidence of these mutations, their impact on biochemical functions including epigenetic modification of genomic DNA and their potential usefulness as prognostic indicators. Importantly, the presence of <italic>DNMT3A</italic>
, <italic>IDH1</italic>
or <italic>IDH2</italic>
mutations may confer sensitivity to novel therapeutic approaches, including the use of demethylating agents. Therefore, the clinical experience with decitabine and azacitidine in the treatment of patients harboring these mutations will be reviewed. Overall, we propose that understanding the role of these mutations in AML biology will lead to more rational therapeutic approaches targeting molecularly defined subtypes of the disease.</p>
</abstract>
</article-meta>
</front>
</pmc>
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