ArticleHaematologica2022
Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia.
Article in Haematologica, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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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.
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Who cites it
30 citing papers in PubMed, 37 citations in OpenAlex.
- A phase 1/2 study of azacitidine, venetoclax and pevonedistat in newly diagnosed secondary AML and in MDS or CMML after failure of hypomethylating agents.Journal of hematology & oncology · 2023Trial
- Dose-Adjusted Treatment With 7-Day Venetoclax Plus Azacitidine or Decitabine in Patients With Acute Myeloid Leukaemia.European journal of haematology · 2026Article
- Pharmacological blockade of rho kinase enhances venetoclax responses in translational models of acute myeloid leukemia.Haematologica · 2026Article
- Targeting the Glutamine Transporter SLC1A5 Enhances Sensitivity of Acute Myeloid Leukemia to MLN4924.Biomedicines · 2026Article
- Decoding neddylation in malignancies: molecular mechanisms, biological functions, therapeutic resistance, and clinical potential.Cell death & disease · 2026Review
- Integrated single-cell and machine learning analysis identifies PMAIP1 as a novel biomarker for predicting prognosis and immunotherapy response in colorectal cancer.Scientific reports · 2025Article
- Combining drugs that bypass p53 to treat TP53-mutated leukemias.Blood advances · 2025Article
- The BCL2 family: from apoptosis mechanisms to new advances in targeted therapy.Signal transduction and targeted therapy · 2025Review
- PMAIP1 regulates the progression of follicular thyroid carcinoma through the Wnt3/FOSL1 pathway.Frontiers in oncology · 2025Article
- Whole exome sequencing and bioinformatics reveal PMAIP1 and PDGFRL as immune-related gene markers in follicular thyroid carcinoma.Frontiers in genetics · 2025Article
- PMAIP1 Enhances DNA Damage and Induces ROS-Mediated Mitochondrial Dysfunction to Suppress Tumorigenesis in Triple-Negative Breast Cancer.The breast journal · 2025Article
- A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia.Haematologica · 2024Article
- CRISPR screen of venetoclax response-associated genes identifies transcription factor ZNF740 as a key functional regulator.Cell death & disease · 2024Article
- Decreased apoptotic priming and loss of BCL-2 dependence are functional hallmarks of Richter's syndrome.Cell death & disease · 2024Article
- Article
- Synergistic cytotoxicity of decitabine and YM155 in leukemia cells through upregulation of SLC35F2 and suppression of MCL1 and survivin expression.Apoptosis : an international journal on programmed cell death · 2024Article
- Meta‑analysis of the efficacy of venetoclax and azacitidine combination therapy and azacitidine monotherapy for treating acute myeloid leukemia.Experimental and therapeutic medicine · 2024Article
- Venetoclax Resistance in Acute Myeloid Leukemia.Cancers · 2024Review
- Venetoclax and Hypomethylating Agent Combination in Myeloid Malignancies: Mechanisms of Synergy and Challenges of Resistance.International journal of molecular sciences · 2023Review
- PLK1 as a cooperating partner for BCL2-mediated antiapoptotic program in leukemia.Blood cancer journal · 2023Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNAmethyltransferase inhibitor (DNMTi), to treat patients with AML. Despite promising response rates to VEN/AZA, resistance to the agent is common. One identified mechanism of resistance is the upregulation of myeloid cell leukemia-1 protein (MCL1). Pevonedistat (PEV), a novel agent that inhibits NEDD8-activating enzyme, and AZA both upregulate NOXA (PMAIP1), a BCL2 family protein that competes with effector molecules at the BH3 binding site of MCL1. We demonstrate that PEV/AZA combination induces NOXA to a greater degree than either PEV or AZA alone, which enhances VEN-mediated apoptosis. Herein, using AML cell lines and primary AML patient samples ex vivo, including in cells with genetic alterations linked to treatment resistance, we demonstrate robust activity of the PEV/VEN/AZA triplet. These findings were corroborated in preclinical systemic engrafted models of AML. Collectively, these results provide rational for combining PEV/VEN/AZA as a novel therapeutic approach in overcoming AML resistance in current therapies.
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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.