Interplay between hypertriglyceridemia and acute promyelocytic leukemia mediated by the cooperation of peroxisome proliferator-activated receptor-α with the PML/RAR α fusion protein on super-enhancers

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 is obscure. Here, we conducted a retrospective study containing 1,412 cases (319 newly diagnosed APL patients, 393 newly diagnosed non-APL acute myeloid leukemia patients, and 700 non-tumor controls) and found that APL patients had higher triglyceride levels than nonAPL (a)nd control groups. Using clinical data, we revealed that hypertriglyceridemia served as a risk factor for early death in APL patients, and there was a positive correlation between triglyceride levels and leukocyte counts. RNA sequencing analysis of APL patients having high or normal triglyceride levels highlighted the contribution of peroxisome proliferator-activated receptor-alpha (PPAR alpha), a crucial regulator of cell metabolism and a transcription factor involved in cancer development. The genome-wide chromatin occupancy of PPARa revealed that PPAR alpha co-existed with PML/RAR alpha within the super-enhancer regions to promote cell proliferation. PPARa knockdown affected the expression of target genes responsible for APL proliferation, including FLT3, and functionally inhibited the proliferation of APL cells. Moreover, in vivo results in mice having high fat diet-induced high triglyceride levels supported the connection between high triglyceride levels and the leukemic burden, as well as the involvement of PPAR alpha-mediated-FLT3 activation in the proliferation of APL cells. Our findings shed light on the association between APL proliferation and high triglyceride levels and provide a genetic link to PPAR alpha-mediated hyperlipidemia in APL.

Automated summary

Patients with newly diagnosed acute promyelocytic leukemia (APL) often have obesity and metabolic disorders, such as dyslipidemia. This study found that APL patients had higher triglyceride levels than non-APL patients and controls. High triglyceride levels were associated with early death in APL patients and positively correlated with leukocyte counts. The involvement of peroxisome proliferator-activated receptor-alpha (PPAR alpha) in APL proliferation and hyperlipidemia was revealed through RNA sequencing analysis and in vivo experiments. This study sheds light on the link between high triglyceride levels and APL proliferation and provides genetic evidence for PPAR alpha-mediated hyperlipidemia in APL.