PXD055730-1

PXD055730 is an original dataset announced via ProteomeXchange.

Title	BRAF inhibitors enhance erythropoiesis and treat anemia through paradoxical activation of MAPK
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.
HostingRepository	iProX
AnnounceDate	2024-09-09
AnnouncementXML	Submission_2024-12-02_18:19:06.485.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yuelin Deng
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-09 01:19:22	ID requested
⏵ 1	2024-12-02 18:19:07	announced

Wu S, Deng Y, Sun H, Liu X, Zhou S, Zhao H, Li H, Guo F, Yue Q, Wu F, Zhao X, Li N, Zhu S, Hu Q, Xie S, Zheng J, Lv M, Kong Y, Huang XJ, Lei X, Tong X, Gao X, Lee HY, BRAF inhibitors enhance erythropoiesis and treat anemia through paradoxical activation of MAPK signaling. Signal Transduct Target Ther, 9(1):338(2024) [pubmed]

submitter keyword: MAPK pathway, BRAF, BRAF inhibitors

Hsiang-Ying Lee
contact affiliation	Peking University
contact email	slee@pku.edu.cn
lab head
Yuelin Deng
contact affiliation	Peking University
contact email	yldeng17@163.com
dataset submitter

iProX dataset URI