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ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control.
Gao, Yimeng; Zimmer, Joshua T; Vasic, Radovan; Liu, Chengyang; Gbyli, Rana; Zheng, Shu-Jian; Patel, Amisha; Liu, Wei; Qi, Zhihong; Li, Yaping; Nelakanti, Raman; Song, Yuanbin; Biancon, Giulia; Xiao, Andrew Z; Slavoff, Sarah; Kibbey, Richard G; Flavell, Richard A; Simon, Matthew D; Tebaldi, Toma; Li, Hua-Bing; Halene, Stephanie.
Afiliação
  • Gao Y; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: gaoym@tongj
  • Zimmer JT; Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06511, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA.
  • Vasic R; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Medicine, Univers
  • Liu C; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
  • Gbyli R; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics and Yale
  • Zheng SJ; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA; Department of Chemistry, Yale University, New Haven, CT 06520, USA.
  • Patel A; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
  • Liu W; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
  • Qi Z; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
  • Li Y; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
  • Nelakanti R; Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
  • Song Y; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Hematologic Oncol
  • Biancon G; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
  • Xiao AZ; Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
  • Slavoff S; Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06511, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA; Department of Chemistry, Yale University, New Haven, CT 06520, USA.
  • Kibbey RG; Department of Internal Medicine, Yale University, New Haven, CT 06520, USA; Department of Cellular & Molecular Physiology, Yale University, New Haven, CT 06520, USA.
  • Flavell RA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • Simon MD; Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06511, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA.
  • Tebaldi T; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular, Computa
  • Li HB; Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • Halene S; Section of Hematology, Department of Internal Medicine, Yale Cancer Center, and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale U
Cell Rep ; 42(10): 113163, 2023 10 31.
Article em En | MEDLINE | ID: mdl-37742191
ABSTRACT
N6-methyladenosine (m6A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m6A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m6A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and instability of oxoglutarate-dehydrogenase (Ogdh) messenger RNA and reduction of OGDH protein levels. Limited OGDH availability slows the tricarboxylic acid (TCA) cycle with accumulation of α-ketoglutarate (α-KG) and conversion of α-KG into L-2-hydroxyglutarate (L-2-HG). L-2-HG inhibits energy production in both murine and human hematopoietic cells in vitro. Impaired mitochondrial energy production confers competitive disadvantage to HSPCs and limits clonogenicity of Mll-AF9-induced leukemia. Our study uncovers a mechanism whereby the RNA m6A demethylase ALKBH5 regulates the stability of metabolic enzyme transcripts, thereby controlling energy metabolism in hematopoiesis and leukemia.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: RNA / Leucemia Limite: Animals / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: RNA / Leucemia Limite: Animals / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2023 Tipo de documento: Article