A5008868238- Acute Myeloid Leukemia Research
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Immune cells in cancer
- Cancer, Lipids, and Metabolism
- Peroxisome Proliferator-Activated Receptors
- Ubiquitin and proteasome pathways
- Cancer Genomics and Diagnostics
- Ferroptosis and cancer prognosis
Xiamen University
2023-2024
First Affiliated Hospital of Xiamen University
2022-2023
Abstract Purpose: Leukemic stem cells (LSC) are responsible for leukemia initiation, relapse, and therapeutic resistance. Therefore, the development of novel approaches targeting LSCs is urgently needed patients with acute myeloid (AML). Experimental Design: The LSC-like cell lines (KG-1α Kasumi-1) CD34+ primary AML purified from (n = 23) treated CS055 and/or chiglitazar were analyzed viability, death, colony formation assay. We performed RNA sequencing, glutamate release, intracellular...
Abstract Persistence of leukemic stem cells (LSCs) is one the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for poor prognosis disease. Hence, novel therapeutic strategies that target LSCs are crucial success. We investigated if targeting Bcl-2 peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate inhibitor venetoclax combined with PPARα agonist chiglitazar...
<div>AbstractPurpose:<p>Leukemic stem cells (LSC) are responsible for leukemia initiation, relapse, and therapeutic resistance. Therefore, the development of novel approaches targeting LSCs is urgently needed patients with acute myeloid (AML).</p>Experimental Design:<p>The LSC-like cell lines (KG-1α Kasumi-1) CD34<sup>+</sup> primary AML purified from (<i>n</i> = 23) treated CS055 and/or chiglitazar were analyzed viability, death, colony...
Background: Leukemia stem cells (LSCs) are responsible for leukemia initiation, relapse, and therapeutic resistance. Therefore, the development of novel approaches targeting LSCs is urgently needed patients with AML.Methods: The LSCs-like cell lines (KG-1α Kasumi-1), CD34+ primary AML purified from (n=23) hematopoietic healthy donors (n=15) were obtained First Affiliated Hospital Xiamen University, Department Hematology. These treated chidamide (CS055) and/or chiglitazar analyzed viability,...
<p>Supplementary Figure S10. A proposed mechanism for the CS055/chiglitazar-induced ferroptosis-like cell death in LSC-like cells by blocking HDAC3-SLC7A11-GSH-GPX4 pathway.</p>
<p>Supplementary Figure S3. (A) The statistical results of fluorescence intensity in CDX mice models (<i>n</i> = 5/group). (B-C) Flow cytometry analysis the percentage hCD45<sup>+</sup> cells bone marrow (B) and spleen (C) (<i>n</i>=3/group). *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001, ****<i>P</i><0.0001.</p>
<p>Supplementary Figure S2. The combination of CS055 and chiglitazar synergistic inhibited AML progression <i>in vivo</i>. (A) Schematic outline the CDX models. (B) Chiglitazar were in mice models (<i>n</i> = 5/group). was measured by living imaging system. (C) Image weight representative spleens from 3/group). (D-E) human CD45 positive cell insulation rate flow cytometry bone marrow (D) spleen (E) (F) improved survival 5/group), animal analyzed using...
<p>Supplementary Figure S6. (A-D) Histone deacetylase activity analysis of HDAC1 (A), HDAC2 (B), HDAC3 (C), and HDAC10 (D) in KG-1α Kasumi-1 cells after treatments with CS055 (4 μM) chiglitazar (16 by HDAC Activity Assay kit. (E) Quantitative real-time PCR SLC7A11 mRNA levels treated and/or for 24 h. (F) Western blotting expression (G) knockdown cells. (H) HDAC3, mutant (H134A H135A) overexpressed data was quantified analyzed Image J Soft. *<i>P</i> < 0.05,...
<p>Supplementary Figure S4. (A) Heatmap of differentially expressed genes involved in ferroptosis KG-1α cells after treatments with CS055 (4 μM) and chiglitazar (16 μM). (B) GSEA analysis for lipid metabolism pathway (C) Cell viability was counted Kasumi-1 erastin (1.875 μM, 3.75 7.5 15 30 24h. (D) Erastin induced the death level cells, cell measured by PI staining analyzed flow cytometry. (E) treated (3.75 24h stained C11-BODIPY endogenous peroxidation (F-G) The glutamate release (F)...
<p>Supplementary Figure S7. (A) Knockdown of HDAC3 enhanced the endogenous lipid peroxidation levels in KG-1α and Kasumi-1cells, was detected by flow cytometry using C11-BODIPY staining. (B-C) The glutamate release (B) intracellular GSH (C) were knockdown Kasumi-1 cells. (D) Cell viability counted cells after treatments Ferr-1 (2 μM) for 72 h. *<i>P</i> < 0.05, **<i>P</i> 0.01, ***<i>P</i> 0.001, ****<i>P</i> 0.0001.</p>
<p>Supplementary Figure S1. (A-B) The CD34<sup>+</sup>CD38<sup>−</sup>cell population was sorted from LSC-like cell lines KG-1α (A) and Kasumi-1 (B) further identified by flow cytometry using CD123, CD96, CD47, CD44, CD32, CD25 antibodies. (C) Flow cytometric plots show the gating strategy to determine percentages of death.</p>
<p>Supplementary Figure S8. (A) The CD34<sup>+</sup> and CD34- primary AML cells identified by flow cytometry using CD34, CD38, CD123, CD96, CD47, CD44, CD32, CD25 antibodies. (B) quantitative analysis for Western blotting of HDAC3, SLC7A11, GPX4 expression in (<i>n</i> = 20) hematopoietic blood stem (HBSCs; <i>n</i> 15). (C-D) HDAC3 protein levels were positively correlated with SLC7A11 (C) 20), but not (D). western data was measured image J...
<p>Supplementary Figure S5. The chiglitazar activates PPARα and transcriptionally represses HDAC3 expression. (A-B) Western blotting analysis of PPARα, HDAC1,2,3, 10 expressions in KG-1α Kasumi-1 cells treated with CS055 and/or for 24 h removed dead by Dead Cell Removal kit. (C-E) (C-D) quantitative real-time PCR (E) (4 μM, 8 16 μM) h. (F) significantly inhibit the transcriptional activity gene promoter (G) ChIP assay analyzed recruitment on HADC3 (16 data was quantified Image J Soft....
<p>Supplementary Figure S9. (A-B) Representative data for flow cytometric analysis of mCD45/hCD34 staining in the spleen (A) and bone marrow (B). (C) Flow cytometry human CD34<sup>+</sup> AML cells sorted from PDX#1 PDX#2 mice by CD34 Nanobeads.</p>
Abstract Leukemia stem cells (LSCs) are responsible for leukemia initiation, relapse, and therapeutic resistance. Therefore, the development of novel approaches targeting LSCs is urgently needed patients with AML. Here, we report that histone deacetylase inhibitor chidamide (CS055), in combination peroxisome proliferator-activated receptor (PPAR) pan agonist (chiglitazar), synergistically targets stem-like from cell lines patient samples, while sparing normal hematopoietic progenitor cells....