PML-RAR? interaction with TRIB3 impedes PPAR?/RXR function and triggers dyslipidemia in acute promyelocytic leukemia.

ABSTRACT: Although dyslipidemia commonly occurs in patients with acute promyelocytic leukemia (APL) in response to anti-APL therapy, the underlying mechanism and the lipid statuses of patients with newly diagnosed APL remain to be addressed. Methods: We conducted a retrospective study to investigate the lipid profiles of APL patients. PML-RAR? transgenic mice and APL cells-transplanted mice were used to assess the effects of APL cells on the blood/liver lipid levels. Subsequently, gene set enrichment analysis, western blot and dual luciferase reporter assay were performed to examine the role and mechanism of PML-RAR? and TRIB3 in lipid metabolism regulation in APL patients at pretreatment and after induction therapy. Results: APL patients exhibited a higher prevalence of dyslipidemia before anti-APL therapy based on a retrospective study. Furthermore, APL cells caused secretion of triglycerides, cholesterol, and PCSK9 from hepatocytes and degradation of low-density lipoprotein receptors in hepatocytes, which elevated the lipid levels in APL cell-transplanted mice and Pml-Rar? transgenic mice. Mechanistically, pseudokinase TRIB3 interacted with PML-RAR? to inhibit PPAR? activity by interfering with the interaction of PPAR? and RXR and promoting PPAR? degradation. Thus, reduced PPAR? activity in APL cells decreased leptin but increased resistin expression, causing lipid metabolism disorder in hepatocytes and subsequent dyslipidemia in mice. Although arsenic/ATRA therapy degraded PML-RAR? and restored PPAR? expression, it exacerbated dyslipidemia in APL patients. The elevated TRIB3 expression in response to arsenic/ATRA therapy suppressed PPAR? activity by disrupting the PPAR?/RXR dimer, which resulted in dyslipidemia in APL patients undergoing therapy. Indeed, the PPAR activator not only enhanced the anti-APL effects of arsenic/ATRA by suppressing TRIB3 expression but also reduced therapy-induced dyslipidemia in APL patients. Conclusion: Our work reveals the critical role of the PML-RAR?/PPAR?/TRIB3 axis in the development of dyslipidemia in APL patients, potentially conferring a rationale for combining ATRA/arsenic with the PPAR activator for APL treatment.

SUBMITTER: Li K 

PROVIDER: S-EPMC7481410 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature