title: Loss of c-Kit and bone marrow failure upon conditional removal of the GATA-2 C-terminal zinc finger domain in adult mice.
abstract: Heterozygous mutations in the transcriptional regulator GATA-2 associate with multilineage immunodeficiency, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). The majority of these mutations localize in the zinc finger (ZnF) domains, which mediate GATA-2 DNA binding. Deregulated hematopoiesis with GATA-2 mutation frequently develops in adulthood, yet GATA-2 function in the bone marrow remains unresolved. To investigate this, we conditionally deleted the GATA-2 C-terminal ZnF (C-ZnF) coding sequences in adult mice. Upon Gata2 C-ZnF deletion, we observed rapid peripheral cytopenia, bone marrow failure, and decreased c-Kit expression on hematopoietic progenitors. Transplant studies indicated GATA-2 has a cell-autonomous role in bone marrow hematopoiesis. Moreover, myeloid lineage populations were particularly sensitive to Gata2 hemizygosity, while molecular assays indicated GATA-2 regulates c-Kit expression in multilineage progenitor cells. Enforced c-Kit expression in Gata2 C-ZnF-deficient hematopoietic progenitors enhanced myeloid colony activity, suggesting GATA-2 sustains myelopoiesis via a cell intrinsic role involving maintenance of c-Kit expression. Our results provide insight into mechanisms regulating hematopoiesis in bone marrow and may contribute to a better understanding of immunodeficiency and bone marrow failure associated with GATA-2 mutation.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Haiyan S
authors.initials: HS
authors.lastname: Li
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Liang
authors.affiliation: Section of Pediatric Infectious Diseases and the Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Matatall
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Ullrich
authors.affiliation: Section of Pediatric Infectious Diseases and the Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Katherine Y
authors.initials: KY
authors.lastname: King
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
mesh_terms: D000741:Anemia, Aplastic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000818:Animals; D015415:Biomarkers; D001853:Bone Marrow / Q000473:pathology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001855:Bone Marrow Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000080983:Bone Marrow Failure Disorders; D001842:Bone and Bones / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D003649:Decalcification, Pathologic / Q000235:genetics; D004195:Disease Models, Animal; D050989:GATA2 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D005787:Gene Frequency; D017930:Genes, Reporter; D005838:Genotype; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D059014:High-Throughput Nucleotide Sequencing; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D011379:Prognosis; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000172:deficiency*; D017384:Sequence Deletion; D058985:Side-Population Cells; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D015415:Biomarkers; D050989:GATA2 Transcription Factor; D019009:Proto-Oncogene Proteins c-kit
keywords: GATA-2 mutation; c-Kit; hematopoiesis; myelopoiesis