GSE195776
A novel interplay between triglycerides and acute promyelocytic leukemia mediated by the cooperation between PPARa and PML/RARa. [CUT&Tag]
Patients with newly diagnosed acute promyelocytic leukemia (APL) are often obese or overweight, accompanied by metabolic disorders, such as dyslipidemia. However, the link between dyslipidemia and leukemia development is obscure. Here, we conducted a retrospective study containing 1,412 medical records (319 APL, 393 non-APL acute myeloid leukemia (AML), and 700 non-tumor controls) and found that APL patients had higher triglyceride levels than non-APL AML and non-tumor controls. We revealed that triglyceride served as a risk factor of early death in APL patients, and there was a positive correlation between high triglyceride levels and high leukocyte counts. RNA-seq analysis on APL patients with high or normal triglyceride levels brought attention to peroxisome proliferator-activated receptor-alpha (PPARa) signaling, a crucial regulator of cell metabolism and a transcription factor involved in cancer development. We demonstrated that PPARa knockdown inhibited the proliferation of APL cells. Chromatin mapping data analysis with CUT&Tag revealed that PPARa coexisted with PML/RARa within the super-enhancer regions to maintain APL. Interventions to PPARa affected the transcription and protein level of FLT3. Moreover, in vivo results in mice having high-fat diet-induced high triglyceride levels supported the connection between high triglyceride levels and the leukemia burden, as well as the involvement of PPARa-mediated-FLT3 activation in the proliferation of APL cells. Our findings shed light on the association between APL cell proliferation and high triglyceride levels and established the contribution of an hyperlipidemia–PPARa–FLT3 axis to APL development. Overall design: CUT&Tag of PPARa and PML/RARA in NB4 cells.