Good, J. D. | Search bioRxiv

bioRxiv2025

An Inflammatory and Quiescent HSC Subpopulation Expands with Age in Humans

Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map revealed previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NF{kappa}B, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.

cell biology↗

bioRxiv2024

Translation Initiation Represents an Acute Myeloid Leukemia Cell Vulnerability That Can Be Co-Targeted With BCL-2 Inhibition

Targeted therapies like Venetoclax have increased the options available to acute myeloid leukemia (AML) patients, but survival remains poor due to drug resistance and disease relapse. We found that the translation initiation factor EIF4A1, which unwinds complex mRNA structures in the 5 UTR of oncogenic transcripts, is highly expressed in AML stem- and progenitor-like cells. Inhibiting eIF4A with the small molecule Zotatifin reduces translation of transcripts related to the cell cycle and survival. This results in downregulation of AKT, STAT-5, and MCL-1 and underlies synergy of Zotatifin with Venetoclax. The drug combination promotes apoptosis across AML genotypes, while the effect on healthy blood cells is limited. Using in vivo relapsed and refractory AML patient-derived xenograft models, the combination significantly suppressed tumor burden and prolonged survival of xenografted mice. These results support eIF4A-mediated protein translation as a therapeutic target in AML. SIGNIFICANCEDespite advances in targeted therapies, the 5-year survival rate for acute myeloid leukemia remains around 32%. The efficacy of existing treatments may be improved with the addition of Zotatifin, an inhibitor targeting the translation initiation factor eIF4A.

cancer biology↗