Therapeutic activation of PPARα contributes to NOTCH1 inhibition in T-cell acute lymphoblastic leukemia.

Abstract

The aberrant activation of the NOTCH1 signaling pathway underlies the aggressive malignancy and poor prognosis of T-cell acute lymphoblastic leukemia (T-ALL). T-ALL cell lines (Jurkat and Molt4) were treated with chiglitazar to evaluate viability, proliferation, apoptosis, and cell cycle. RNA-seq, qRT-PCR, and Western blotting were used to examine NOTCH1 signaling. Mechanistic assays included luciferase reporter, DNA affinity precipitation, co-immunoprecipitation, and ChIP. In vivo, cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models were generated by intravenous engraftment of leukemic cells into sublethally irradiated mice, followed by treatment with chiglitazar alone or combined with venetoclax. Therapeutic efficacy was assessed by survival, flow cytometric tumor burden, and histopathology (HE and IHC). We report that therapeutic activation of peroxisome proliferator-activated receptor α (PPARα) significantly represses the leukemogenesis of T-ALL in vitro and in vivo by blocking the NOTCH1 signaling pathway. Mechanistically, PPARα directly binds to the promoter region of the NOTCH1 gene and inhibits its transcriptional activity. Furthermore, PPARα interacts with signal transducer and activator of transcription 3 (STAT3) and attenuates the transcriptional activation effect of STAT3 on the NOTCH1 gene promoter. Importantly, we also found that therapeutic activation of PPARα using chiglitazar synergizes with venetoclax to suppress T-ALL progression in PDX models. We conclude that targeting PPARα to suppress T-ALL progression by blocking the NOTCH1 pathway represents a potential novel therapeutic strategy for the treatment of T-ALL.