High-fat diet promotes Acute Promyelocytic Leukemia through PPARδ-enhanced self-renewal of preleukemic progenitors

Abstract

AbstractObesity is associated with a higher risk of developing many cancer types including acute promyelocytic leukaemia (APL), a subset of acute myeloid leukemias (AML) characterized by expression of the PML-RARα oncogene. The molecular mechanisms linking obesity and APL development are not known. To model clinical observations, we established a mouse model of diet-induced obesity using transgenic mice constitutively expressing PML-RARA α in the hematopoietic system (PML-RARα KI mice) fed either standard (SD) or high-fat (HFD) diets. HFD-fed PML-RARα KI mice developed leukaemia with reduced latency and increased penetrance, as compared to SD-fed mice. HFD leads to accumulation of DNA damage in hematopoietic stem cells (HSCs), but, surprisingly, this was not associated with mutational load gain, as shown by whole genome/exome sequencing of pre-leukemic and leukemic cells. Importantly, very few of the observed mutations were predicted to act as cancer drivers, suggesting the relevance of nongenetic mechanisms. HFD led to an expansion of hematopoietic progenitor cells with a concomitant reduction in long-term hematopoietic stem cells, and in the presence of PML-RARα this was also accompanied by an enhancement of in vitro and in vivo self-renewal. Interestingly, Linoleic Acid (LA), abundant in HFD, recapitulates the effect of HFD on the self-renewal of PML-RARα HPCs by activating the peroxisome proliferator-activated receptor delta (PPARδ), a central regulator of fatty acid metabolism involved in the promotion of cancer progression. Our findings have implications for dietary or pharmacological interventions aimed at counteracting the cancer-promoting effect of obesity.Key pointshigh fat diet (HFD) promotes APL leukemogenesis in mouse models, reproducing the exquisite sensitivity to obesity observed in humansalthough HFD leads to DNA damage and mutations, the molecular mechanism is nongenetic and linked to the transcription factor PPARδ