Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells
Identifieur interne : 003038 ( Main/Exploration ); précédent : 003037; suivant : 003039Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells
Auteurs : Susumu Goyama [États-Unis] ; Janet Schibler [États-Unis] ; Lea Cunningham [États-Unis] ; Yue Zhang [États-Unis] ; Yalan Rao [États-Unis] ; Nahoko Nishimoto [Japon] ; Masahiro Nakagawa [Japon] ; Andre Olsson [États-Unis] ; Mark Wunderlich [États-Unis] ; Kevin A. Link [États-Unis] ; Benjamin Mizukawa [États-Unis] ; H. Leighton Grimes [États-Unis] ; Mineo Kurokawa [Japon] ; P. Paul Liu [États-Unis] ; Gang Huang [États-Unis] ; James C. Mulloy [États-Unis]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2013.
Abstract
RUNX1 is generally considered a tumor suppressor in myeloid neoplasms. Inactivating RUNX1 mutations have frequently been found in patients with myelodysplastic syndrome (MDS) and cytogenetically normal acute myeloid leukemia (AML). However, no somatic RUNX1 alteration was found in AMLs with leukemogenic fusion proteins, such as core-binding factor (CBF) leukemia and MLL fusion leukemia, raising the possibility that RUNX1 could actually promote the growth of these leukemia cells. Using normal human cord blood cells and those expressing leukemogenic fusion proteins, we discovered a dual role of RUNX1 in myeloid leukemogenesis. RUNX1 overexpression inhibited the growth of normal cord blood cells by inducing myeloid differentiation, whereas a certain level of RUNX1 activity was required for the growth of AML1-ETO and MLL-AF9 cells. Using a mouse genetic model, we also showed that the combined loss of
Url:
DOI: 10.1172/JCI68557
PubMed: 23979164
PubMed Central: 3754260
Affiliations:
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last="Goyama">Susumu Goyama</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Schibler, Janet" sort="Schibler, Janet" uniqKey="Schibler J" first="Janet" last="Schibler">Janet Schibler</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Cunningham, Lea" sort="Cunningham, Lea" uniqKey="Cunningham L" first="Lea" last="Cunningham">Lea Cunningham</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Oncogenesis and Development Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Oncogenesis and Development Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Zhang, Yue" sort="Zhang, Yue" uniqKey="Zhang Y" first="Yue" last="Zhang">Yue Zhang</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Rao, Yalan" sort="Rao, Yalan" uniqKey="Rao Y" first="Yalan" last="Rao">Yalan Rao</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Nishimoto, Nahoko" sort="Nishimoto, Nahoko" uniqKey="Nishimoto N" first="Nahoko" last="Nishimoto">Nahoko Nishimoto</name><affiliation wicri:level="4"><nlm:aff id="JCI68557">Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Japon</country><wicri:regionArea>Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region><settlement type="city">Tokyo</settlement></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Nakagawa, Masahiro" sort="Nakagawa, Masahiro" uniqKey="Nakagawa M" first="Masahiro" last="Nakagawa">Masahiro Nakagawa</name><affiliation wicri:level="4"><nlm:aff id="JCI68557">Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Japon</country><wicri:regionArea>Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region><settlement type="city">Tokyo</settlement></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Olsson, Andre" sort="Olsson, Andre" uniqKey="Olsson A" first="Andre" last="Olsson">Andre Olsson</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Wunderlich, Mark" sort="Wunderlich, Mark" uniqKey="Wunderlich M" first="Mark" last="Wunderlich">Mark Wunderlich</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Link, Kevin A" sort="Link, Kevin A" uniqKey="Link K" first="Kevin A." last="Link">Kevin A. Link</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Mizukawa, Benjamin" sort="Mizukawa, Benjamin" uniqKey="Mizukawa B" first="Benjamin" last="Mizukawa">Benjamin Mizukawa</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Grimes, H Leighton" sort="Grimes, H Leighton" uniqKey="Grimes H" first="H. Leighton" last="Grimes">H. Leighton Grimes</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Kurokawa, Mineo" sort="Kurokawa, Mineo" uniqKey="Kurokawa M" first="Mineo" last="Kurokawa">Mineo Kurokawa</name><affiliation wicri:level="4"><nlm:aff id="JCI68557">Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Japon</country><wicri:regionArea>Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region><settlement type="city">Tokyo</settlement></placeName><orgName type="university">Université de Tokyo</orgName></affiliation></author><author><name sortKey="Liu, P Paul" sort="Liu, P Paul" uniqKey="Liu P" first="P. Paul" last="Liu">P. Paul Liu</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Oncogenesis and Development Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Oncogenesis and Development Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Huang, Gang" sort="Huang, Gang" uniqKey="Huang G" first="Gang" last="Huang">Gang Huang</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Mulloy, James C" sort="Mulloy, James C" uniqKey="Mulloy J" first="James C." last="Mulloy">James C. Mulloy</name><affiliation wicri:level="2"><nlm:aff id="JCI68557">Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><idno type="eISSN">1558-8238</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>RUNX1 is generally considered a tumor suppressor in myeloid neoplasms. Inactivating RUNX1 mutations have frequently been found in patients with myelodysplastic syndrome (MDS) and cytogenetically normal acute myeloid leukemia (AML). However, no somatic RUNX1 alteration was found in AMLs with leukemogenic fusion proteins, such as core-binding factor (CBF) leukemia and MLL fusion leukemia, raising the possibility that RUNX1 could actually promote the growth of these leukemia cells. Using normal human cord blood cells and those expressing leukemogenic fusion proteins, we discovered a dual role of RUNX1 in myeloid leukemogenesis. RUNX1 overexpression inhibited the growth of normal cord blood cells by inducing myeloid differentiation, whereas a certain level of RUNX1 activity was required for the growth of AML1-ETO and MLL-AF9 cells. Using a mouse genetic model, we also showed that the combined loss of <italic>Runx1/Cbfb</italic> inhibited leukemia development induced by MLL-AF9. RUNX2 could compensate for the loss of RUNX1. The survival effect of RUNX1 was mediated by BCL2 in MLL fusion leukemia. Our study unveiled an unexpected prosurvival role for RUNX1 in myeloid leukemogenesis. Inhibiting RUNX1 activity rather than enhancing it could be a promising therapeutic strategy for AMLs with leukemogenic fusion proteins.
</p></div></front></TEI><affiliations><list><country><li>Japon</li><li>États-Unis</li></country><region><li>Maryland</li><li>Ohio</li><li>Région de Kantō</li></region><settlement><li>Tokyo</li></settlement><orgName><li>Université de Tokyo</li></orgName></list><tree><country name="États-Unis"><region name="Ohio"><name sortKey="Goyama, Susumu" sort="Goyama, Susumu" uniqKey="Goyama S" first="Susumu" last="Goyama">Susumu Goyama</name></region><name sortKey="Cunningham, Lea" sort="Cunningham, Lea" uniqKey="Cunningham L" first="Lea" last="Cunningham">Lea Cunningham</name><name sortKey="Grimes, H Leighton" sort="Grimes, H Leighton" uniqKey="Grimes H" first="H. Leighton" last="Grimes">H. Leighton Grimes</name><name sortKey="Grimes, H Leighton" sort="Grimes, H Leighton" uniqKey="Grimes H" first="H. Leighton" last="Grimes">H. Leighton Grimes</name><name sortKey="Huang, Gang" sort="Huang, Gang" uniqKey="Huang G" first="Gang" last="Huang">Gang Huang</name><name sortKey="Link, Kevin A" sort="Link, Kevin A" uniqKey="Link K" first="Kevin A." last="Link">Kevin A. Link</name><name sortKey="Liu, P Paul" sort="Liu, P Paul" uniqKey="Liu P" first="P. Paul" last="Liu">P. Paul Liu</name><name sortKey="Mizukawa, Benjamin" sort="Mizukawa, Benjamin" uniqKey="Mizukawa B" first="Benjamin" last="Mizukawa">Benjamin Mizukawa</name><name sortKey="Mulloy, James C" sort="Mulloy, James C" uniqKey="Mulloy J" first="James C." last="Mulloy">James C. Mulloy</name><name sortKey="Olsson, Andre" sort="Olsson, Andre" uniqKey="Olsson A" first="Andre" last="Olsson">Andre Olsson</name><name sortKey="Rao, Yalan" sort="Rao, Yalan" uniqKey="Rao Y" first="Yalan" last="Rao">Yalan Rao</name><name sortKey="Schibler, Janet" sort="Schibler, Janet" uniqKey="Schibler J" first="Janet" last="Schibler">Janet Schibler</name><name sortKey="Wunderlich, Mark" sort="Wunderlich, Mark" uniqKey="Wunderlich M" first="Mark" last="Wunderlich">Mark Wunderlich</name><name sortKey="Zhang, Yue" sort="Zhang, Yue" uniqKey="Zhang Y" first="Yue" last="Zhang">Yue Zhang</name></country><country name="Japon"><region name="Région de Kantō"><name sortKey="Nishimoto, Nahoko" sort="Nishimoto, Nahoko" uniqKey="Nishimoto N" first="Nahoko" last="Nishimoto">Nahoko Nishimoto</name></region><name sortKey="Kurokawa, Mineo" sort="Kurokawa, Mineo" uniqKey="Kurokawa M" first="Mineo" last="Kurokawa">Mineo Kurokawa</name><name sortKey="Nakagawa, Masahiro" sort="Nakagawa, Masahiro" uniqKey="Nakagawa M" first="Masahiro" last="Nakagawa">Masahiro Nakagawa</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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