title: Runx1 Deficiency Decreases Ribosome Biogenesis and Confers Stress Resistance to Hematopoietic Stem and Progenitor Cells.
abstract: The transcription factor RUNX1 is frequently mutated in myelodysplastic syndrome and leukemia. RUNX1 mutations can be early events, creating preleukemic stem cells that expand in the bone marrow. Here we show, counterintuitively, that Runx1-deficient hematopoietic stem and progenitor cells (HSPCs) have a slow growth, low biosynthetic, small cell phenotype and markedly reduced ribosome biogenesis (Ribi). The reduced Ribi involved decreased levels of rRNA and many mRNAs encoding ribosome proteins. Runx1 appears to directly regulate Ribi; Runx1 is enriched on the promoters of genes encoding ribosome proteins and binds the rDNA repeats. Runx1-deficient HSPCs have lower p53 levels, reduced apoptosis, an attenuated unfolded protein response, and accordingly are resistant to genotoxic and ER stress. The low biosynthetic activity and corresponding stress resistance provides a selective advantage to Runx1-deficient HSPCs, allowing them to expand in the bone marrow and outcompete normal HSPCs.
authors.affiliation: Abramson Family Cancer Research Institute, Institute for Regenerative Medicine and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Teng
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Jingping
authors.initials: J
authors.lastname: Ge
authors.affiliation: Abramson Family Cancer Research Institute, Institute for Regenerative Medicine and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Zaw Min
authors.initials: ZM
authors.lastname: Oo
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Kumar
authors.affiliation: Abramson Family Cancer Research Institute, Institute for Regenerative Medicine and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Mason
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Tan
authors.affiliation: Abramson Family Cancer Research Institute, Institute for Regenerative Medicine and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: nancyas@exchange.upenn.edu.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Speck
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D050676:Core Binding Factor Alpha 2 Subunit / Q000172:deficiency* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009153:Mutagens / Q000633:toxicity; D001678:Organelle Biogenesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D009153:Mutagens; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D016159:Tumor Suppressor Protein p53; D058570:TOR Serine-Threonine Kinases