Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Acquired non-genetic resistance mechanisms to existing therapies contribute to poor outcomes for acute myeloid leukemia (AML) patients, and inability to target leukemic stem cells (LSCs) can lead to relapse. To overcome these challenges, we tested whether LSCs have dependencies on PI3 kinase (PI3K). We found that LSCs are susceptible to isoform-selective targeting of PI3K and are particularly dependent on the P110 alpha isoform of PI3K. We discovered that PI3K inactivation leads to dynamic changes in EZH2/PRC2 function in leukemic cells, and we uncovered downregulation of EZH2 protein levels as a resistance mechanism in response to PI3K inhibition. We found that PI3K inhibition in AML cells can lead to compensatory upregulation of EZH1, and that EZH1 knockdown can sensitize AML cells to PI3K inhibition. We leveraged this resistance mechanism by combining a PI3K inhibitor with an EZH1/2 dual inhibitor, which successfully overcomes the acquired resistance and leads to sustained targeting of AML cells ex vivo and in murine AML and PDX models in vivo. This study identifies a promising novel therapeutic regimen for targeting LSCs in AML.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12338508 | PMC |
| http://dx.doi.org/10.1101/2025.07.11.663968 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
High-Intensity Exercise and Hippocampal Integrity in Adults With Cannabis Use Disorder: A Randomized Clinical Trial.
JAMA Psychiatry
September 2025
School of Psychological Sciences, Monash University, Melbourne, Victoria, Australia.
Importance: Cannabis is the most commonly used illicit drug, with 10% to 30% of regular users developing cannabis use disorder (CUD), a condition linked to altered hippocampal integrity. Evidence suggests high-intensity interval training (HIIT) enhances hippocampal structure and function, with this form of physical exercise potentially mitigating CUD-related cognitive and mental health impairments.
Objective: To determine the impact of a 12-week HIIT intervention on hippocampal integrity (ie, structure, connectivity, biochemistry) compared with 12 weeks of strength and resistance (SR) training in CUD.
The composition, influencing factors, and physiological functions of bifidobacteria in the infant gut: a review.
Food Funct
September 2025
College of Food Science, Southwest University, Chongqing, 400715, China.
Bifidobacteria are naturally found in the human gut and quickly establish dominance shortly after birth, playing a crucial role in the development and stability of the infant gut microbiota. A growing body of research suggests that host and environmental factors shape the colonization and the relative abundance of bifidobacteria in the infant gut during early life. Understanding the factors that influence bifidobacterial colonization and maintaining normal colonization levels are keys to ensuring gut health.
View Article and Find Full Text PDFThe effect of CD40 agonist antibody therapy on the pancreatic cancer microenvironment.
Naunyn Schmiedebergs Arch Pharmacol
September 2025
Department of Gastroenterology, Jinhua Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, Zhejiang, China.
The fourth leading cause of cancer-related fatalities in the USA is pancreatic ductal adenocarcinoma (PDAC), a particularly deadly illness that is resistant to immunotherapy. One of the Main Obstacles in cancer research is developing better treatments for PDAC, which has the lowest 5-year survival rate of any malignancy. Anti-CTLA-4, anti-PD-L1, and anti-PD-1 immune checkpoint blockade medications also have poor results in these patients, which may indicate the presence of other immunosuppressive mechanisms in the pancreatic tumor microenvironment (TME).
View Article and Find Full Text PDFNovel Strategies to Conquer Residual Adiposity Risk in Cardiovascular Disease.
Curr Atheroscler Rep
September 2025
Department of Cardiology, Houston Methodist DeBakey Heart and Vascular Center, Houston, TX, USA.
Purpose Of Review: Despite major advances in the treatment and prevention of atherosclerotic cardiovascular disease (ASCVD), a substantial burden of residual risk remains Obesity has been redefined as a primary and independent drivers of cardiovascular morbidity and mortality warranting focused attention.
Recent Findings: Obesity is now recognized as a chronic disease and a central contributor to residual cardiovascular risk through mechanisms including systemic inflammation, insulin resistance, dyslipidemia, and endothelial dysfunction. This review addresses the limitations of conventional obesity management and highlights emerging pharmacological therapies targeting the underlying adiposopathy.
Surface Properties of Colloidal Quantum-Confined One-Dimensional Lepidocrocite Titanates: Insights into their Ion-Induced Gelation.
Langmuir
September 2025
Department of Materials Science and Engineering, Drexel University, Philadelphia, Pennsylvania 19104, United States.
The surfaces of 1D layered lepidocrocite-structured titanates (1DLs) are negatively charged due to an oxygen-to-titanium atomic ratio >2. This, and their layered structure, allow for facile ion exchange and high colloidal stability, demonstrated by ζ-potentials of ≈ -85 mV at their unadjusted pH of ≈10.4.
View Article and Find Full Text PDF