Dataset Information

The PML domain of PML-RAR? blocks senescence to promote leukemia.

ABSTRACT: In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein-retinoic acid receptor ? (PML-RAR?) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML-RAR? (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19(ARF) cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx-histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.

SUBMITTER: Korf K

PROVIDER: S-EPMC4143011 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The PML domain of PML-RARα blocks senescence to promote leukemia.

Korf Katharina K Wodrich Harald H Haschke Alexander A Ocampo Corinne C Harder Lena L Gieseke Friederike F Pollmann Annika A Dierck Kevin K Prall Sebastian S Staege Hannah H Ma Hui H Horstmann Martin A MA Evans Ronald M RM Sternsdorf Thomas T

Proceedings of the National Academy of Sciences of the United States of America 20140804 33

In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein-retinoic acid receptor α (PML-RARα) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML-RARα (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, w ...[more]

PMID: 25092303

Similar Datasets

Project description: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-RARα 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-RARα 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-Rarα transgenic mice. Mechanistically, pseudokinase TRIB3 interacted with PML-RARα to inhibit PPARγ activity by interfering with the interaction of PPARγ and RXR and promoting PPARγ degradation. Thus, reduced PPARγ 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-RARα and restored PPARγ expression, it exacerbated dyslipidemia in APL patients. The elevated TRIB3 expression in response to arsenic/ATRA therapy suppressed PPARγ activity by disrupting the PPARγ/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-RARα/PPARγ/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.

Dataset Information

The PML domain of PML-RAR? blocks senescence to promote leukemia.

Publications

The PML domain of PML-RARα blocks senescence to promote leukemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets