Dataset Information

Leukemia stem cells defend ferroptosis by controlling cystine uptake via PIEZO1-HIF1A-SLC7A11 axis

ABSTRACT: Metabolism reprogramming is intimately accompanied with mitochondrial oxidative stress in driving many human diseases including cancers. Excessive oxidative stress frequently induces cell death including ferroptosis, which needs to be tightly balanced for maintaining cellular homeostasis. However, the precise mechanisms for balancing metabolic reprogramming and oxidative stress under different contexts remain elusive. Here, by studying acute myeloid leukemia stem cells (LSCs) that are largely fueled by OXPHOS, we reveal a defense system of LSCs against oxidative stress-induced ferroptosis. We find that the mechano-sensor PIEZO1 plays key role in promoting acute myeloid leukemia development and maintaining LSCs stemness. PIEZO1 deletion impairs cystine uptake and induces ROS and lipid peroxidation, causing ferroptosis of leukemia cells. Mechanistically, HIF1A mediates the function of PIEZO1 by transcriptionally regulating the expression of SLC7A11 and SLC3A2. Further, inhibition of PIEZO1 and SLC7A11 suppresses LSC function and contributes to AML treatment. In summary, our findings reveal that LSCs control cystine uptake through PIEZO1-HIF1A-SLC7A11 axis to defend ferroptosis, representing a unique vulnerability of LSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE313852 | GEO | 2026/07/15

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Purpose: Leukemia stem cells (LSCs) are responsible for leukemia initiation, relapse, and therapeutic resistance. Therefore, the development of novel therapeutic approaches targeting LSCs is urgently needed for patients with AML. Methods: The LSCs-like cell lines (KG-1α and Kasumi-1), CD34+ primary AML cells purified from AML patients (n=23) treated with CS055 and/or chiglitazar and were analyzed for viability, death, and colony formation assay. We performed RNA-seq, Glutamate-Release, Intracellular-GSH, Lipid-ROS, transmission-electron-microscopy, Western-Blotting assay, and confirmed ferroptosis in LSCs-like cells. The luciferase-reporter, co-immunoprecipitation, HDAC3-shRNA/HDAC3/deacetylase-deficient LSCs-like cell lines, His-pull-down, and chromatin-immunoprecipitation assays performed to clarify the molecular mechanism of CS055/chiglitazar in LSCs-like cells. We also established CDX and PDX mouse models to evaluate the therapeutic efficacy of CS055/chiglitazar against-AML in vivo. Results: We report that the histone deacetylase inhibitor CS055, in combination with peroxisome proliferator-activated receptor (PPAR) pan-agonist (chiglitazar), synergistically targets leukemia stem-like cells from leukemia cell lines and patient samples, while sparing normal hematopoietic progenitor cells. Mechanistically, chiglitazar enhances the inhibitory effect of CS055 on HDAC3 and induces ferroptosis in LSCs-like cells by down-regulating the expression of ferroptosis suppressor SLC7A11. In fact, the inhibition of HDAC3 increases H3K27AC levels in the promoter region of activating transcription factor 3 (ATF3), a transcriptional repressor of the SLC7A11 gene, and upregulates the expression of ATF3. In contrast, ATF4, a SLC7A11 activator, is suppressed by HDAC3 inhibition. Conclusions: Our findings suggest that treatment with CS055 combined with chiglitazar, will target LSCs by inducing ferroptosis and may confer an effective approach for the treatment of AML.

Dataset Information

Leukemia stem cells defend ferroptosis by controlling cystine uptake via PIEZO1-HIF1A-SLC7A11 axis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets