ArticleBlood2023
Activation of the PP2A-B56α heterocomplex synergizes with venetoclax therapies in AML through BCL2 and MCL1 modulation.
Article in Blood, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 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
15 citing papers in PubMed, 22 citations in OpenAlex.
- The protein phosphatase 2A-B56α complex regulates N-Myc degradation in neuroblastoma.The Journal of biological chemistry · 2026Article
- Switching of the c-Myc protein degradation pathway depending on the PP2A-B55α complex levels.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Therapy-Induced Senescence (TIS) and SASP: The p53-Mediated Interplay in Cancer Progression and Treatment.International journal of molecular sciences · 2025Review
- The multiplex crosstalk between non-coding RNAs, programmed cell death and related mechanisms: a dynamic duo in hematological malignancies.Cancer cell international · 2025Review
- Talazoparib and radiation enhance the senolytic efficacy of venetoclax in therapy-induced senescent triple-negative breast cancer cells.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2025Article
- [Bioinformatic analysis of venetoclax sensitivity and resistance mechanisms in acute myeloid leukemia].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2025Article
- Advances in the application of patient-derived xenograft models in acute leukemia resistance.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Ferroptosis: a novel pharmacological mechanism against multiple myeloma.Frontiers in pharmacology · 2025Review
- Drug delivery for age-related bone diseases: From therapeutic targets to common and emerging therapeutic strategies.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2024Review
- Concomitant targeting of FLT3 and SPHK1 exerts synergistic cytotoxicity in FLT3-ITDCell communication and signaling : CCS · 2024Article
- Emerging Roles of B56 Phosphorylation and Binding Motif in PP2A-B56 Holoenzyme Biological Function.International journal of molecular sciences · 2024Review
- Altering phosphorylation in cancer through PP2A modifiers.Cancer cell international · 2024Review
- Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies.The Journal of clinical investigation · 2023Article
- PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis.The Journal of clinical investigation · 2023Article
- Inhibition of adaptive therapy tolerance in cancer: is triplet mitochondrial targeting the key?Molecular oncology · 2023Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
16 authors at 5 institutions in 2 countries.
Funding
Abstract
Venetoclax combination therapies are becoming the standard of care in acute myeloid leukemia (AML). However, the therapeutic benefit of these drugs in older/unfit patients is limited to only a few months, highlighting the need for more effective therapies. Protein phosphatase 2A (PP2A) is a tumor suppressor phosphatase with pleiotropic functions that becomes inactivated in ∼70% of AML cases. PP2A promotes cancer cell death by modulating the phosphorylation state in a variety of proteins along the mitochondrial apoptotic pathway. We therefore hypothesized that pharmacological PP2A reactivation could increase BCL2 dependency in AML cells and, thus, potentiate venetoclax-induced cell death. Here, by using 3 structurally distinct PP2A-activating drugs, we show that PP2A reactivation synergistically enhances venetoclax activity in AML cell lines, primary cells, and xenograft models. Through the use of gene editing tools and pharmacological approaches, we demonstrate that the observed therapeutic synergy relies on PP2A complexes containing the B56α regulatory subunit, of which expression dictates response to the combination therapy. Mechanistically, PP2A reactivation enhances venetoclax-driven apoptosis through simultaneous inhibition of antiapoptotic BCL2 and extracellular signal-regulated kinase signaling, with the latter decreasing MCL1 protein stability. Finally, PP2A targeting increases the efficacy of the clinically approved venetoclax and azacitidine combination in vitro, in primary cells, and in an AML patient-derived xenograft model. These preclinical results provide a scientific rationale for testing PP2A-activating drugs with venetoclax combinations in AML.
Indexed as
Identifiers
What Socratic 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 Socratic graph.