Page 63 - Haematologica April 2020

Hematopoiesis
RUNX3 levels in human hematopoietic progenitors are regulated by aging and dictate erythroid-myeloid balance
Peter Balogh,1 Emmalee R. Adelman,2 John V. Pluvinage,3 Brian J. Capaldo,4 Katie C. Freeman,1 Sandeep Singh,1 Kamaleldin E. Elagib,1
Yukio Nakamura,5 Ryo Kurita,6 Goro Sashida,7 Eli R. Zunder,8 Hui Li,1 Alejandro A. Gru,1 Elizabeth A. Price,9 Stanley L. Schrier,9
Irving L. Weissman,10 Maria E. Figueroa,2 Wendy W. Pang,11* and Adam N. Goldfarb1*
1Department of Pathology, University of Virginia School of Medicine, Charlottesville, USA; 2Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, Florida, USA; 3Department of Medicine, Stanford University, Stanford, California, USA; 4Flow Cytometry Core Facility, University of Virginia School of Medicine, Charlottesville, Virginia, USA; 5Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan; 6Research and Development Department, Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tatsumi, Koto-ku, Tokyo, Japan; 7Laboratory of Transcriptional Regulation in Leukemogenesis IRCMS, Kumamoto University, Chuo-ku, Kumamoto, Japan; 8Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA; 9Department of Medicine, Division of Hematology, Stanford University, Stanford, California, USA; 10Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA and 11Department of Medicine, Division of Blood and Bone Marrow Transplantation, Stanford University, Stanford, California, USA
*WWP and ANG contributed equally to this work
ABSTRACT
Healthy bone marrow progenitors yield a co-ordinated balance of hematopoietic lineages. This balance shifts with aging toward enhanced granulopoiesis with diminished erythropoiesis and lym- phopoiesis, changes which likely contribute to the development of bone marrow disorders in the elderly. In this study, RUNX3 was identified as a hematopoietic stem and progenitor cell factor whose levels decline with aging in humans and mice. This decline is exaggerated in hematopoietic stem and progenitor cells from subjects diagnosed with unexplained ane- mia of the elderly. Hematopoietic stem cells from elderly unexplained ane- mia patients had diminished erythroid but unaffected granulocytic colony forming potential. Knockdown studies revealed human hematopoietic stem and progenitor cells to be strongly influenced by RUNX3 levels, with modest deficiencies abrogating erythroid differentiation at multiple steps while retaining capacity for granulopoiesis. Transcriptome profiling indi- cated control by RUNX3 of key erythroid transcription factors, including KLF1 and GATA1. These findings thus implicate RUNX3 as a participant in hematopoietic stem and progenitor cell aging, and a key determinant of ery- throid-myeloid lineage balance.
Introduction
Hematopoietic stem and progenitor cells (HSPC) execute tightly co-ordinated self-renewal and lineage commitment programs that generate a balanced output of peripheral blood cell types. With aging, these programs undergo perturbation resulting in increased numbers and decreased function within the stem cell com- partment as well as a shift in the balance of cell types produced – namely, an increased proportion of granulocytes at the expense of erythroid and lymphoid lin- eages.1-4 Thus normal aged mice have diminished peripheral red blood cells and lymphocytes, increased circulating neutrophils and monocytes, and increased sen- sitivity to granulocyte-colony stimulating factor (G-CSF)-induced leukocytosis and HSPC mobilization.5,6 The transplantability of age-related HSPC changes highlights
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):905-913
Correspondence:
ADAM N. GOLDFARB
ang3x@virginia.edu
Received: October 19, 2018. Accepted: June 5, 2019. Pre-published: June 6, 2019.
doi:10.3324/haematol.2018.208918
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/905
©2020 Ferrata Storti Foundation
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