Journal
CELL REPORTS
Volume 37, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.110036
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Funding
- National Cancer Institute [R01CA255996, R01CA188471, R21CA187857, CA246707]
- McCormick Genomic and Proteomic Center of George Washington University
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ARID4B interferes with KITLG/KIT signaling, promoting HSC differentiation instead of self-renewal. ARID4B-deficient HSCs self-express KITLG and overexpress KIT, leading to differentiation. Inhibition of Src family kinases rescues the HSC differentiation defect caused by ARID4B loss.
Balance between the hematopoietic stem cell (HSC) duality to either possess self-renewal capacity or differentiate into multipotency progenitors (MPPs) is crucial for maintaining homeostasis of the hematopoietic stem/progenitor cell (HSPC) compartment. To retain the HSC self-renewal activity, KIT, a receptor tyrosine kinase, in HSCs is activated by its cognate ligand KITLG originating from niche cells. Here, we show that AT-rich interaction domain 4B (ARID4B) interferes with KITLG/KIT signaling, consequently allowing HSC differentiation. Conditional Arid4b knockout in mouse hematopoietic cells blocks fetal HSC differentiation, preventing hematopoiesis. Mechanistically, ARID4B-deficient HSCs self-express KITLG and overexpress KIT. As to downstream pathways of KITLG/KIT signaling, inhibition of Src family kinases rescues the HSC differentiation defect elicited by ARID4B loss. In summary, the intrinsic ARID4B-KITLG/KIT-Src axis is an HSPC regulatory program that enables the differentiation state, while KIT stimulation by KITLG from niche cells preserves the HSPC undifferentiated pool.
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