Abstract
AbstractThe transcription factor GATA2 has pivotal roles in hematopoiesis. Germline GATA2 mutations result in GATA2 haploinsufficiency characterized by immunodeficiency, bone marrow failure and predispositions to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical symptoms in GATA2 patients are diverse and mechanisms driving GATA2 related phenotypes are largely unknown. To explore the impact of GATA2 haploinsufficiency on hematopoiesis, we generated a zebrafish model carrying a heterozygous mutation in gata2b, an orthologue of GATA2. Morphological analysis revealed progression of myeloid and erythroid dysplasia in gata2b+/- kidney marrow (KM). Single cell RNA sequencing on KM cells showed that the erythroid dysplasia in gata2b+/- zebrafish was preceded by a differentiation block in erythroid progenitors, hallmarked by downregulation of cytoskeletal transcripts, aberrant proliferative signatures and ribosome biogenesis. Additionally, transcriptional and functional analysis of Gata2b haploinsufficient hematopoietic stem cells (HSCs) indicated that proliferative stress within the HSC compartment possibly contributes to the development of myeloid and erythroid dysplasia in gata2b+/- zebrafish.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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