ArticleThe Journal of experimental medicine2013
Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies.
Article in The Journal of experimental medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 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
56 citing papers in PubMed, 85 citations in OpenAlex.
- Predictors of Early Death in Acute Promyelocytic Leukemia.Medical sciences (Basel, Switzerland) · 2025Review
- Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation.Nature · 2025Article
- Discovery of an LSD1 PROTAC degrader.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- ALLG APML5: bioavailability and safety of oral arsenic trioxide assessed during consolidation therapy for APL.Blood advances · 2025Article
- Diagnostic and Therapeutic Implications of the SUMOylation Pathway in Acute Myeloid Leukemia.Cancers · 2025Review
- Acute Promyelocytic Leukemia, Retinoic Acid, and Arsenic: A Tale of Dualities.Cold Spring Harbor perspectives in medicine · 2024Review
- Targeted protein degradation: from mechanisms to clinic.Nature reviews. Molecular cell biology · 2024Review
- Pin1-catalyzed conformational regulation after phosphorylation: A distinct checkpoint in cell signaling and drug discovery.Science signaling · 2024Review
- History of Developing Acute Promyelocytic Leukemia Treatment and Role of Promyelocytic Leukemia Bodies.Cancers · 2024Review
- USP22 regulates APL differentiation via PML-RARα stabilization and IFN repression.Cell death discovery · 2024Article
- Induced protein degradation for therapeutics: past, present, and future.The Journal of clinical investigation · 2024Review
- UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.Molecular cell · 2023Article
- Vitamin A and retinoid signaling in the kidneys.Pharmacology & therapeutics · 2023Review
- The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out Nor Fading Away.Cancers · 2023Review
- Co-targeting leukemia-initiating cells and leukemia bulk leads to disease eradication.Leukemia · 2022Article
- The role of E2A in ATPR-induced cell differentiation and cycle arrest in acute myeloid leukaemia cells.Journal of cellular and molecular medicine · 2022Article
- Review
- A PML/RARα direct target atlas redefines transcriptional deregulation in acute promyelocytic leukemia.Blood · 2021Article
- Non-genetic heterogeneity, altered cell fate and differentiation therapy.EMBO molecular medicine · 2021Review
- IGFBP7 activates retinoid acid-induced responses in acute myeloid leukemia stem and progenitor cells.Blood advances · 2020Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In PML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell differentiation and transiently clears the disease. Molecularly, RA activates PML/RARA-dependent transcription and also initiates its proteasome-mediated degradation. In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specifically targeting its PML moiety. The respective contributions of RA-triggered transcriptional activation and proteolysis to clinical response remain disputed. Here, we identify synthetic retinoids that potently activate RARA- or PML/RARA-dependent transcription, but fail to down-regulate RARA or PML/RARA protein levels. Similar to RA, these uncoupled retinoids elicit terminal differentiation, but unexpectedly fail to impair leukemia-initiating activity of PML/RARA-transformed cells ex vivo or in vivo. Accordingly, the survival benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by RA. Differentiated APL blasts sorted from uncoupled retinoid-treated mice retain PML/RARA expression and reinitiate APL in secondary transplants. Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential. These observations unify the modes of action of RA and arsenic and shed light on the potency of their combination in mice or patients.
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.