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2739 Fzr1 Preserves Hematopoietic Stem Cell Quiescence through Inhibiting Runx1

Program: Oral and Poster Abstracts
Session: 502. Hematopoiesis: Regulation of Gene Transcription, Cytokines, Signal Transduction, Apoptosis, and Cell Cycle Regulation: Poster III
Hematology Disease Topics & Pathways:
Animal models, Biological Processes, Study Population, hematopoiesis, pathways, proteomics
Monday, December 7, 2020, 7:00 AM-3:30 PM

Chengfang Zhou1*, Mei Kuang1*, Jieping Chen2* and Yu Hou, PhD3

1Southwest Hospital, Third Military Medical University (Army Medical University), ChongQing, China
2Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
3Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), CHONGQING, China

Regulated blood production is achieved through the hierarchical organization of dormant hematopoietic stem cell (HSC) subsets that differ in self-renewal potential and division frequency, with long-term (LT)-HSCs dividing the least. FZR1, as a regulatory subunit of anaphase promoting complex/cyclosome (APC), is a master regulator of cell cycle, but little is known with regard to its role in HSC quiescence. Thus, we examined the function of Fzr1 in HSCs during steady-state hematopoiesis and under stress. We demonstrate that Fzr1 deletion led to perturbed hematopoiesis with an approximately 2-fold decrease in HSC pool size, as consequence of Fzr1 loss driving HSC from quiescence into rapid cycling (~70.1% to ~28.4%), elevating proliferation (~4.58% to ~18.5%) and apoptosis (~0.23% to ~2.86%) in HSC. As shown by serial bone marrow transplantation and competitive repopulation assays, self-renewal capacity and regenerative capacity were impaired, but differentiation of HSCs was not affected post Fzr1 deletion. Mechanistically, Fzr1 loss led to upregulation of Runx1 expression, in line with the protein expression, the ubiquitin sites of the gene was also obviouly decreased, knockdown Runx1 can rescue the Fzr1-deficient phenotype in HSC. Together, our data therefore support that Fzr1 acts a positive regulator of HSC quiescence and self-renewal capacity through inhibiting Runx1 expression.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH