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.
Subject(s)
Anemia, Aplastic/genetics , Bone Marrow Diseases/genetics , Bone Marrow/pathology , GATA2 Transcription Factor/genetics , Hemoglobinuria, Paroxysmal/genetics , Protein Interaction Domains and Motifs/genetics , Proto-Oncogene Proteins c-kit/deficiency , Sequence Deletion , Zinc Fingers/genetics , Anemia, Aplastic/diagnosis , Anemia, Aplastic/metabolism , Anemia, Aplastic/mortality , Animals , Biomarkers , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Bone Marrow Diseases/diagnosis , Bone Marrow Diseases/metabolism , Bone Marrow Diseases/mortality , Bone Marrow Failure Disorders , Bone and Bones/pathology , Chromatin Immunoprecipitation , Decalcification, Pathologic/genetics , Disease Models, Animal , GATA2 Transcription Factor/chemistry , GATA2 Transcription Factor/metabolism , Gene Expression , Gene Expression Regulation , Gene Frequency , Genes, Reporter , Genotype , Hematopoiesis/genetics , Hematopoietic Stem Cells/metabolism , Hemoglobinuria, Paroxysmal/diagnosis , Hemoglobinuria, Paroxysmal/metabolism , Hemoglobinuria, Paroxysmal/mortality , High-Throughput Nucleotide Sequencing , Immunophenotyping , Mice , Mice, Knockout , Prognosis , Side-Population CellsABSTRACT
Three new cases of DOOR syndrome are described in unrelated Brazilian children. One of these cases also has a congential cardiac defect. None of the cases has organic acid abnormalities and they can therefore be classified as Type II.
