-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2733 Prdm16 Is a Critical Regulator of Adult Long-Term Hematopoietic Stem Cell Quiescence

Program: Oral and Poster Abstracts
Session: 501. Hematopoietic Stem and Progenitor Biology: Poster III
Hematology Disease Topics & Pathways:
cell division, Biological Processes, hematopoiesis
Monday, December 7, 2020, 7:00 AM-3:30 PM

Kristbjorn Orri Gudmundsson, PhD1*, Yang Du, PhD1, Nhu Nguyen1*, Kevin Oakley1*, Yufen Han1*, Bjorg Gudmundsdottir2*, Pentao Liu3*, Lino Tessarollo4*, Nancy Jenkins5* and Neal Copeland5*

1Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD
2NHLBI, NIH, Bethesda, MD
3School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong
4CCR-NCI, Mouse Cancer Genetics Program, Frederick
5The University of Texas MD Anderson Cancer Center, Houston, TX

Regulation of quiescence is critical for the maintenance of adult hematopoietic stem cells (HSCs). PRDM16 encodes a zinc-finger transcription factor homologous to MECOM and was first cloned from chromosome translocations in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Disruption of Prdm16 during mouse embryonic development has been shown to cause a profound loss of fetal liver HSCs; however, the underlying mechanisms and the function of Prdm16 in adult HSCs remain unclear. Using a novel Prdm16 conditional knockout mouse model, we show that Prdm16 deletion in adult mouse hematopoietic system have a less severe effect on HSCs, causing a gradual decline in adult HSC numbers and a concomitant increase in the multipotent progenitor (MPP) compartment. Prdm16 deletion in the hematopoietic system following transplantation produced the same phenotype indicating that the defect is intrinsic to adult HSCs. This HSC loss was also exacerbated by stress induced by 5-FU injections. Annexin V staining showed no difference in apoptosis between wild type and knockout adult long-term HSCs (LT-HSCs). In contrast, BrdU analysis revealed that loss of Prdm16 significantly increases cycling of LT-HSCs with majority of the cells found in the S to G2/M phase. Consistently, RNA-seq analysis of mouse LT-HSCs with and without Prdm16 deletion showed that Prdm16 loss induced a significant decrease in the expression of several known cell cycle regulators of HSCs. Two such genes were further identified as direct targets of Prdm16. Our results suggest that Prdm16 preserves the function of adult LT-HSCs by promoting their quiescence.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH