Investigate Drl and Blf genome-wide occupancy in zebrafish hematopoietic progenitors with CUT&Tag
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE212060 | GEO | 2022/09/01
REPOSITORIES: GEO
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Project description:Investigate Drl and Blf genome-wide occupancy in zebrafish hematopoietic progenitors with CUT&Tag
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Project description:Erythropoiesis is a crucial part in hematopoietic system, while facing disruptions from various diseases conditions. Anemia and blood shortages has become global challenges, with current finite pharmacological options like EPO or glucocorticoids having limitations, especially in genetic anemias like Diamond-Blackfan anemia (DBA), calling for novel candidates in stimulating the erythropoiesis. We designed the primary human hematopoietic stem and progenitor cells (HSPCs) chemicals screening system in erythropoiesis and unexpectedly discovered a BRAF inhibitor, effectively against BRAFV600E mutant cancers, delaying erythroid differentiation while promoting progenitors’ proliferation. Further research demonstrated its efficacy in cytokine-restricted conditions and in samples from erythroid disorder patients. Mechanistically, BRAF inhibitors paradoxically activated the RAF-MEK-ERK/MAPK pathway. Unlike oncogenic BRAFV600E impaired hematopoiesis and erythropoiesis via AP-1 hyperactivation, BRAF inhibitors minimally affected HSPCs self-renewal and differentiation. In vivo studies further exhibited BRAF inhibitors' potential to enhance human hematopoiesis and erythropoiesis in severe immunodeficient mouse models and alleviate anemia symptoms in Rpl11 haploinsufficiency DBA models and other anemia models. This discovery sheds light on the MAPK pathway's role in hematopoiesis, making BRAF inhibitors a novel clinically therapeutic choice in improving hematopoietic reconstitution and the recovery of anemias like DBA.
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