Vroeg in de Wei, G. | bioRxiv Science

bioRxiv2026

Time-resolved single-cell state tracing exposes bidirectional state dynamics during differentiation

Differentiation dynamics have been challenging to study across time as measuring cell state, transcriptionally or epigenetically, typically requires its destruction. Here, we developed single-cell state tracing using the DCM-Time machine to enable the characterization of two transcriptomes, separated in time in single cells during epithelial cell differentiation in the intestine of living animals, and during neuronal differentiation in culture. We show that retrospective transcriptional histories and current states are consistent with bidirectional movements along differentiation trajectories both in vivo and in vitro that become rarer as cells mature. Furthermore, we observe rare transcriptome conversions, across canonical lineage boundaries. Our data support a model in which differentiating cells occasionally fail to stabilize lineage-associated programs, enabling reversals and subsequent resolution toward alternative lineage states.

developmental biology↗

bioRxiv2023

Imetelstat-Mediated Alterations in Fatty Acid Metabolism To Induce Ferroptosis As Therapeutic Strategy for Acute Myeloid Leukemia

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft (PDX) resource, and perform integrated genomics, transcriptomics, and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized Phase II-like preclinical trial in PDX, imetelstat effectively diminishes AML burden, and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing significant disease control in AML.

cancer biology↗