BRAF inhibitors enhance erythropoiesis and treat anemia through paradoxical activation of MAPK signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA913585 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22801687_1.fastq.gz | Fastqsanger.gz | |||
| SRR22801687_2.fastq.gz | Fastqsanger.gz | |||
| SRR22801688_1.fastq.gz | Fastqsanger.gz | |||
| SRR22801688_2.fastq.gz | Fastqsanger.gz | |||
| SRR22801689_1.fastq.gz | Fastqsanger.gz |
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Project description:Erythropoiesis is a crucial process in hematopoiesis, yet it remains highly susceptible to disruption by various diseases, which significantly contribute to the global challenges of anemia and blood shortages. Current treatments like erythropoietin (EPO) or glucocorticoids often fall short, especially for hereditary anemias such as Diamond-Blackfan anemia (DBA). To uncover new erythropoiesis-stimulating agents, we devised a screening system using primary human hematopoietic stem and progenitor cells (HSPCs). We discovered that BRAF inhibitors (BRAFi), commonly used to treat BRAFV600E melanoma, can unexpectedly and effectively promote progenitor cell proliferation by temporarily delaying erythroid differentiation. Notably, these inhibitors exhibited pronounced efficacy even under cytokine-restricted conditions and in patient samples of DBA. Mechanistically, although these BRAFi inhibit the MAPK cascade in BRAFV600E mutant cells, they paradoxically act as amplifiers in wild-type BRAF cells, potently enhancing the cascade. Furthermore, we found that while the oncogenic BRAFV600E mutation disrupts hematopoiesis and erythropoiesis through AP-1 hyperactivation, BRAFi minimally impact HSPC self-renewal and differentiation. In vivo studies have shown that BRAFi can enhance human hematopoiesis and erythropoiesis in severe immunodeficient mouse models and alleviate anemia in the Rpl11 haploinsufficiency DBA model, as well as other relevant anemia models. This discovery underscores the role of the MAPK pathway in hematopoiesis and positions BRAFi as a promising therapeutic option for improving hematopoietic reconstitution and treating anemias, including DBA.
2024-12-02 | GSE221242 | GEO
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.
2024-09-09 | PXD055730 |
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.
2024-12-03 | GSE275226 | GEO
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.
2024-12-03 | GSE261117 | GEO
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.
2024-12-03 | GSE261118 | GEO
Project description:BRAF activation enhances erythropoiesis and treats anemia
| PRJNA1149830 | ENA
Project description:BRAF inhibitors promote erythropoiesis and hematopoiesis via paradoxical MAPK activation
| PRJNA1085310 | ENA
Project description:BRAF inhibitors promote erythropoiesis and hematopoiesis via paradoxical MAPK activation (ATAC-Seq)
| PRJNA1085317 | ENA
Project description:BRAF inhibitors promote erythropoiesis and hematopoiesis via paradoxical MAPK activation (RNA-Seq)
| PRJNA1085318 | ENA
Project description:Study was performed to improve understanding of erythropoiesis (EP) induced by acute anemia in Atlantic salmon. Fish was injected with a low dose of hemolytic compound phenylhydrazine (PHZ). Treatment resulted in moderate but significant reduction of hematocrit (Hct) and increased transcription of cardiac erythropoietin (epo) at 2 days post challenge (dpc), and epo receptor (epor) in spleen from 2 to 4 dpc. Oligonucleotide microarrays were used to characterize the events of EP in the spleen. These results were compared to gene expression profiles of untreated mature red blood cells (RBC) in order to search for erythroid-specific genes. Splenic responses suggested a prevalence of protective mechanisms at the first stage, characterized by induced xenobiotic metabolism and responses to oxidative and protein stress. Erythroid-specific regulation was evident at 2 dpc and enhanced by 4 dpc, and gene expression profiles witnessed a rapid establishment of RBC phenotype although Hct levels remained low. A large group of genes showed a strong correlation to globins by expression profiles. In addition to epor this included genes of heme and iron metabolism, scavengers of free radicals and chaperones, channels and transporters, markers of erythrocytes, regulators of proliferation and cell cycle arrest and many genes with unidentified roles in RBC differentiation. Induced EP in spleen was characterized by specific features, such as upregulation of virus-responsive genes and sustained high expression of proapoptotic genes including caspases. Transcriptome changes suggested an association between EP and suppression of several developmental programs including adaptive immune responses. In conclusion, acute hemolysis and resulting anemia rapidly induced EP in the spleen of Atlantic salmon, which showed both common characteristics for all vertebrates as well as fish-specific properties. Atlantic salmon was injected with a single dose of PHZ (6 mg/kg body mass) or saline. Spleen samples for microarray analyses were collected after 2 and 4 days. Additonally, red blood cells (RBC) were compared with spleen
2013-03-26 | E-GEOD-45479 | biostudies-arrayexpress