ArticleBlood advances2025
Combining drugs that bypass p53 to treat TP53-mutated leukemias.
Article in Blood advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
5 citing papers in PubMed.
- Treatment ofHaematologica · 2026Trial
- Global bibliometric analysis of TP53-mutated acute myeloid leukemia: research hotspots and evolution.Translational cancer research · 2026Article
- AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.Molecular cancer · 2026Article
- Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- AcTor, a novel mTOR stimulator, potentiates ixazomib for the treatment of acute myeloid leukemia.Research square · 2026Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
abstractAcute myeloid leukemias (AML) containing TP53 (p53) mutations are routinely treated with decitabine or 5-azacytidine, which deplete DNA methyltransferase 1 (DNMT1; ie, hypomethylating agents [HMA]). Unfortunately, resistance/relapse, characterized by preserved DNMT1, is rapid. HMA are pyrimidine analogs, and to deplete DNMT1, must compete with endogenous pyrimidines. These were substantially increased in HMA-resistant vs parental AML cells, together with upregulation of CAD (carbamoyl-phosphate-synthetase-2/aspartate transcarbamylase/dihydroorotase) that rate limits de novo pyrimidine synthesis. Moreover, TP53-mutated AML appeared primed for such resistance, with higher baseline CAD. Pyrimidine synthesis can be depowered with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax to release BCL-2-associated X protein (BAX) to depolarize mitochondrial membranes. However, BAX, a p53 target gene, was substantially less expressed in TP53-mutated vs wild-type TP53 cells, and venetoclax impacts were correspondingly limited. Alternatively, pyrimidine synthesis can be inhibited directly at dihydroorotate dehydrogenase (DHODH) using the clinical drug teriflunomide. Contrasting with venetoclax, teriflunomide decreased pyrimidine levels several-fold, restored DNMT1 depletion, and cytoreduced HMA-resistant TP53-mutated AML cells via p53/apoptosis-independent terminal-differentiation. This noncytotoxic pathway preserved viability and proliferation of normal hematopoietic stem/progenitor cells (NHSPCs). Inhibiting pyrimidine synthesis triggered compensatory pyrimidine salvage, such that schedules for teriflunomide combination with HMA, which are taken up by salvage, mattered. In mice with TP53-mutated AML, teriflunomide scheduled the day before HMA was more efficacious than same-day or day-after schedules. Chronic teriflunomide exposure paradoxically increased pyrimidines via sustained compensatory salvage, conferring resistance rather than sensitivity to HMA. In sum, DNMT1 and DHODH targeting, administered by timed, intermittent (metronomic) schedules, can circumvent genetic resistance caused by TP53 mutations and adaptive resistance caused by metabolic homeostasis, without cytotoxicity to HSPCs.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.