Novel Therapeutic Combining CS055 with Chiglitazar Targets Leukemia Stem and Progenitor Cells in Acute Myeloid Leukemia

Failure to completely eliminate leukemic stem cells (LSC) is the major factor in treatment failure and relapse in acute myeloid leukemia (AML). Therefore, the development of chemotherapeutic agents targeting LSC is imperative for patients with AML. Here, we report that the combination of the histone deacetylase inhibitor chidamide (CS055) and peroxisome proliferator-activated receptor (PPAR) pan agonist (chiglitazar) has a synergistic killing effect on CD34⁺CD38^- leukemia stem-like cells and primary CD34⁺ AML cells in vitro while sparing normal hematopoietic progenitor cell. Besides, the combination regimen inhibits the tumorigenic progression of AML in the patient-derived xenograft (PDX) mouse models driven by primary CD34⁺ AML cells generated from AML patients. Mechanistically, chiglitazar enhances the inhibitory effect of CS055 on HDAC3 and combines with CS055 to induce ferroptosis in CD34⁺CD38^- leukemia stem-like cells by suppressing SLC7A11 expression. Moreover, the inhibition of HDAC3 increases the H3K27ac levels in the promoter region of activating transcription factor 3 (ATF3) and upregulates the expression of ATF3, which is the transcriptional repressor of the SLC7A11 gene. Meanwhile, down-regulation of HDAC3 expression or deficiency of the deacetylase activity can suppress the transcriptional activation effects of activating transcription factor 4 (ATF4) on the SLC7A11 gene. Thus, we conclude that this combination regimen of CS055 and chiglitazar serves as a new therapeutic approach to enhance the elimination of leukemia stem and progenitor cells in AML treatment.

No relevant conflicts of interest to declare.