title: Stress hematopoiesis is regulated by the Krüppel-like transcription factor ZBP-89.
abstract: Previous studies have shown that ZBP-89 (Zfp148) plays a critical role in erythroid lineage development, with its loss at the embryonic stage causing lethal anemia and thrombocytopenia. Its role in adult hematopoiesis has not been described. We now show that conditional deletion of ZBP-89 in adult mouse hematopoietic stem/progenitor cells (HSPC) causes anemia and thrombocytopenia that are transient in the steady state, but readily uncovered following chemically induced erythro/megakaryopoietic stress. Unexpectedly, stress induced by bone marrow transplantation of ZBP89(-/-) HSPC also resulted in a myeloid-to-B lymphoid lineage switch in bone marrow recipients. The erythroid and myeloid/B lymphoid lineage anomalies in ZBP89(-/-) HSPC are reproduced in vitro in the ZBP-89-silenced multipotent hematopoietic cell line FDCP-Mix A4, and are associated with the upregulation of PU.1 and downregulation of SCL/Tal1 and GATA-1 in ZBP89-deficient cells. Chromatin immunoprecipitation and luciferase reporter assays show that ZBP-89 is a direct repressor of PU.1 and activator of SCL/Tal1 and GATA-1. These data identify an important role for ZBP-89 in regulating stress hematopoiesis in adult mouse bone marrow.
authors.affiliation: Leukocyte Biology & Inflammation Program, Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Xiangen
authors.initials: X
authors.lastname: Li
authors.forename: Rachael D
authors.initials: RD
authors.lastname: Romain
authors.forename: Dongsu
authors.initials: D
authors.lastname: Park
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Juanita L
authors.initials: JL
authors.lastname: Merchant
authors.forename: M Amin
authors.initials: MA
authors.lastname: Arnaout
mesh_terms: D000375:Aging / Q000473:pathology; D000740:Anemia / Q000150:complications / Q000473:pathology; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D045744:Cell Line, Tumor; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004920:Erythropoiesis; D050982:GATA1 Transcription Factor / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013312:Stress, Physiological; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013921:Thrombocytopenia / Q000150:complications / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D050982:GATA1 Transcription Factor; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C489366:Tal1 protein, mouse; C491741:Zfp148 protein, mouse
keywords: Erythroid progenitors; Hematopoietic stem cells; Stress hematopoiesis; Transcription factors; Transplantation