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Preprint WatchMildOctober 10th, 2026

Perturbation of the replication stress-ATR axis accelerates human erythroid differentiation but blocks terminal maturation

Jauregui-Lozano, J.; Kremer, A.; Prummel, K. D.; Zaugg, J. B.

Inhibition of ATR, but not ATM or DNA-PK, accelerates erythroid commitment while blocking terminal maturation, reframing chemotherapy-associated anemia as a differentiation defect rather than progenitor depletion

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

This preprint reports that inhibition of ATR, but not ATM or DNA-PK, accelerates erythroid commitment while blocking terminal maturation in cord-blood CD34+ progenitors, reframing chemotherapy-associated anemia as a differentiation defect rather than progenitor depletion. Claidex holds one ATR failure, ceralasertib-atr-advanced-solid-tumours-phase1-programme-discontinuation, which ended as a strategic reprioritization rather than on efficacy or toxicity grounds. The mechanism described here gives a concrete account of why hematologic tolerability constrains ATR inhibitor dosing, and it predicts that red cell deficits track with pathway engagement rather than with cumulative progenitor loss. For programs still dosing ATR inhibitors, that distinction is testable with enucleation readouts in ex vivo erythroid cultures before a dose-escalation design is locked.

Abstract excerpt

Replication stress (RS) can act as an input to differentiation: in erythroid and myeloid cells it is sufficient to accelerate commitment. Yet genotoxic chemotherapy, which imposes replication stress on the bone marrow can cause anemia; a frequent dose-limiting toxicity whose deficit of mature red cells is often attributed to progenitor depletion rather than to any effect on differentiation itself. Here, we ask how RS-induced accelerated commitment gives rise to impaired red cell output, using in vitro erythroid differentiation of cord-blood CD34+ progenitors perturbed with clinically relevant chemotherapy agents. We find that treated erythroblasts differentiate faster than controls but fail to mature, measured by lack of enucleated cells. Inhibition of ATR, but not ATM or DNA-PK, reproduces this phenotype. Mechanistically, single-cell profiling of drug-treated cells shows convergence on a transcriptional program, marked by loss of MYB and MYC activity. Treated cultures also accumulate aberrant late erythroblasts depleted for globin and heme programs and enriched for p53 and proteotoxic stress signatures. Together, these results propose that defective maturation is an alternative mechanism for chemotherapy-induced anemia, in addition to depletion of progenitors.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.