Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy
Identifieur interne : 000410 ( Main/Exploration ); précédent : 000409; suivant : 000411Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy
Auteurs : Ida Sofie Gr Nnings Ter ; Hanne Kristin Fredly ; Bj Rn Tore Gjertsen ; Kimberley Joanne Hatfield [Norvège] ; Ystein BruserudSource :
- Cells [ 2073-4409 ] ; 2019.
Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease for a subset of such patients. We performed untargeted serum metabolomic profiling for 44 AML patients receiving treatment based on ATRA and valproic acid combined with low-dose cytotoxic drugs (cytarabine, hydroxyurea, 6-mercaptopurin) which identified 886 metabolites. When comparing pretreatment samples from responders and non-responders, metabolites mainly belonging to amino acid and lipid (i.e., fatty acid) pathways were altered. Furthermore, patients with rapidly progressive disease showed an extensively altered lipid metabolism. Both ATRA and valproic acid monotherapy also altered the amino acid and lipid metabolite profiles; however, these changes were only highly significant for valproic acid treatment. Twenty-three metabolites were significantly altered by seven-day valproic acid treatment (
Url:
DOI: 10.3390/cells8101229
PubMed: 31658693
PubMed Central: 6829623
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Systemic Metabolomic Profiling of Acute Myeloid Leukemia Patients before and During Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid, Valproic Acid, and Low-Dose Chemotherapy</title><author><name sortKey="Gr Nnings Ter, Ida Sofie" sort="Gr Nnings Ter, Ida Sofie" uniqKey="Gr Nnings Ter I" first="Ida Sofie" last="Gr Nnings Ter">Ida Sofie Gr Nnings Ter</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author><author><name sortKey="Fredly, Hanne Kristin" sort="Fredly, Hanne Kristin" uniqKey="Fredly H" first="Hanne Kristin" last="Fredly">Hanne Kristin Fredly</name><affiliation><nlm:aff id="af3-cells-08-01229">Department of Medicine, Bærum Hospital, 1346 Bærum, Norway;<email>Harfre@vestreviken.no</email></nlm:aff></affiliation></author><author><name sortKey="Gjertsen, Bj Rn Tore" sort="Gjertsen, Bj Rn Tore" uniqKey="Gjertsen B" first="Bj Rn Tore" last="Gjertsen">Bj Rn Tore Gjertsen</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author><author><name sortKey="Hatfield, Kimberley Joanne" sort="Hatfield, Kimberley Joanne" uniqKey="Hatfield K" first="Kimberley Joanne" last="Hatfield">Kimberley Joanne Hatfield</name><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-cells-08-01229">Department of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen, Norway</nlm:aff><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen</wicri:regionArea><wicri:noRegion>5021 Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Bruserud, Ystein" sort="Bruserud, Ystein" uniqKey="Bruserud " first=" Ystein" last="Bruserud"> Ystein Bruserud</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31658693</idno><idno type="pmc">6829623</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829623</idno><idno type="RBID">PMC:6829623</idno><idno type="doi">10.3390/cells8101229</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000476</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000476</idno><idno type="wicri:Area/Pmc/Curation">000476</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000476</idno><idno type="wicri:Area/Pmc/Checkpoint">000370</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000370</idno><idno 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(B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author><author><name sortKey="Fredly, Hanne Kristin" sort="Fredly, Hanne Kristin" uniqKey="Fredly H" first="Hanne Kristin" last="Fredly">Hanne Kristin Fredly</name><affiliation><nlm:aff id="af3-cells-08-01229">Department of Medicine, Bærum Hospital, 1346 Bærum, Norway;<email>Harfre@vestreviken.no</email></nlm:aff></affiliation></author><author><name sortKey="Gjertsen, Bj Rn Tore" sort="Gjertsen, Bj Rn Tore" uniqKey="Gjertsen B" first="Bj Rn Tore" last="Gjertsen">Bj Rn Tore Gjertsen</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author><author><name sortKey="Hatfield, Kimberley Joanne" sort="Hatfield, Kimberley Joanne" uniqKey="Hatfield K" first="Kimberley Joanne" last="Hatfield">Kimberley Joanne Hatfield</name><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af4-cells-08-01229">Department of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen, Norway</nlm:aff><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen</wicri:regionArea><wicri:noRegion>5021 Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Bruserud, Ystein" sort="Bruserud, Ystein" uniqKey="Bruserud " first=" Ystein" last="Bruserud"> Ystein Bruserud</name><affiliation><nlm:aff id="af1-cells-08-01229">Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;<email>Ida.Gronningseter@uib.no</email> (I.S.G.);<email>Bjorn.Gjertsen@uib.no</email> (B.T.G.)</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cells-08-01229">Section for Hematology, Institute of Clinical Science, University of Bergen, 5021 Bergen, Norway;<email>Kimberley.Hatfield@uib.no</email></nlm:aff></affiliation></author></analytic><series><title level="j">Cells</title><idno type="eISSN">2073-4409</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Acute myeloid leukemia (AML) is an aggressive malignancy, and many elderly/unfit patients cannot receive intensive and potentially curative therapy. These patients receive low-toxicity disease-stabilizing treatment. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid can stabilize the disease for a subset of such patients. We performed untargeted serum metabolomic profiling for 44 AML patients receiving treatment based on ATRA and valproic acid combined with low-dose cytotoxic drugs (cytarabine, hydroxyurea, 6-mercaptopurin) which identified 886 metabolites. When comparing pretreatment samples from responders and non-responders, metabolites mainly belonging to amino acid and lipid (i.e., fatty acid) pathways were altered. Furthermore, patients with rapidly progressive disease showed an extensively altered lipid metabolism. Both ATRA and valproic acid monotherapy also altered the amino acid and lipid metabolite profiles; however, these changes were only highly significant for valproic acid treatment. Twenty-three metabolites were significantly altered by seven-day valproic acid treatment (<italic>p</italic> < 0.05, <italic>q</italic> < 0.05), where the majority of altered metabolites belonged to lipid (especially fatty acid metabolism) and amino acid pathways, including several carnitines. These metabolomic effects, and especially the effects on lipid metabolism, may be important for the antileukemic and epigenetic effects of this treatment.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Steffen, B" uniqKey="Steffen B">B. Steffen</name></author><author><name sortKey="Muller Tidow, C" uniqKey="Muller Tidow C">C. Muller-Tidow</name></author><author><name sortKey="Schwable, J" uniqKey="Schwable J">J. Schwable</name></author><author><name sortKey="Berdel, W E" uniqKey="Berdel W">W.E. Berdel</name></author><author><name sortKey="Serve, H" uniqKey="Serve H">H. 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Zaganjor</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Norvège</li></country></list><tree><noCountry><name sortKey="Bruserud, Ystein" sort="Bruserud, Ystein" uniqKey="Bruserud " first=" Ystein" last="Bruserud"> Ystein Bruserud</name><name sortKey="Fredly, Hanne Kristin" sort="Fredly, Hanne Kristin" uniqKey="Fredly H" first="Hanne Kristin" last="Fredly">Hanne Kristin Fredly</name><name sortKey="Gjertsen, Bj Rn Tore" sort="Gjertsen, Bj Rn Tore" uniqKey="Gjertsen B" first="Bj Rn Tore" last="Gjertsen">Bj Rn Tore Gjertsen</name><name sortKey="Gr Nnings Ter, Ida Sofie" sort="Gr Nnings Ter, Ida Sofie" uniqKey="Gr Nnings Ter I" first="Ida Sofie" last="Gr Nnings Ter">Ida Sofie Gr Nnings Ter</name></noCountry><country name="Norvège"><noRegion><name sortKey="Hatfield, Kimberley Joanne" sort="Hatfield, Kimberley Joanne" uniqKey="Hatfield K" first="Kimberley Joanne" last="Hatfield">Kimberley Joanne Hatfield</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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