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Preprint WatchModerateSeptember 16th, 2026

Glucocorticoids reprogram human AML leukemic stem cells to promote elimination through differentiation and apoptosis

Iasenza, I. A.; Sun, Y. L.; Best, L.; Dakik, H.; Boileau, M.; Neumann, A. L.; Arreba-Tutusaus, P.; Saby, M.; Hebert, J.; Minden, M.; Cavallone, L.; Williams, C.; Jean-Claude, B.; Eppert, K.

Glucocorticoids deplete AML leukemic stem cells through the glucocorticoid receptor NR3C1, with receptor binding affinity correlating with anti-LSC activity, supporting clinical development of glucocorticoid-based therapy in AML.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint proposes NR3C1 agonism as a therapeutic axis in acute myeloid leukemia and closes by supporting clinical development of glucocorticoid-based therapy. The Claidex graph carries two NR3C1 clinical failures, both classified as efficacy failures, and both in the opposite pharmacological direction or a different disease: exicorilant, a glucocorticoid receptor antagonist in metastatic castration-resistant prostate cancer (exicorilant-mcrpc-gr-bypass-fourth-failure), and early low-dose hydrocortisone in septic shock, stopped by a data safety monitoring board for futility (early-hydrocortisone-nr3c1-sepsis-siriraj-dsmb-futility-termination). Neither failure tests the AML leukemic stem cell hypothesis directly, so this flag is a base-rate warning rather than a contradiction. What it does say is that NR3C1 is a receptor where target engagement has repeatedly been achievable while clinical benefit has not, in both agonist and antagonist directions, and the preprint's own data are preclinical. The translational step this work still owes is a prospective demonstration that receptor binding affinity predicts leukemic stem cell depletion in patients rather than in LSC-enriched models, with the FLT3 ligand biomarker the authors propose tested prospectively rather than post hoc.

Abstract excerpt

Acute myeloid leukemia (AML) is sustained by leukemic stem cells (LSCs) that can evade standard therapies and drive relapse. Targeting LSC-specific vulnerabilities is therefore essential for durable remission. Here we demonstrate that glucocorticoids (GCs) induce potent depletion of AML LSCs by promoting terminal differentiation and apoptosis. This effect is observable within 24 hours and is conserved across multiple LSC-enriched models and primary patient samples. Mechanistically, we establish that GC targeting of LSCs is mediated through the glucocorticoid receptor (NR3C1), with higher receptor binding affinity correlating with greater anti-LSC activity. We performed structure activity relationship (SAR) modeling of 24 corticosteroids and identified key features, including bulky D-ring substituents, associated with enhanced anti-LSC efficacy. Bulk and single-cell transcriptomic data revealed that GC treatment of LSCs suppresses NF-{kappa}B inflammatory signaling and disrupts stemness and quiescence programs while inducing transcriptional signatures associated with transient proliferation, metabolic stress, and terminal differentiation. Notably, GC sensitivity was associated with the expression of pre-existing inflammatory or extracellular matrix (ECM) signatures. Finally, we found that FLT3 ligand (FLT3L) is required for GC-induced proliferation of CD34- blasts but not for LSC depletion, suggesting that FLT3L levels may serve as a biomarker for blast expansion in patients receiving GC therapy. These findings support the clinical development of GC-based therapies in AML and provide mechanistic insights into how GCs target inflammatory and metabolic programs required for LSC survival.

Matching Claidex post-mortems

2 of 2 indexed

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.