ROLE OF OBESITY IN THE DEVELOPMENT OF ACUTE PROMYELOCYTIC LEUKEMIA (APL)

Obesity is a pathological condition characterized by an augmented presence of fat mass in the body, and a known risk factor for many cancer types. Clinical data have shown that the incidence of acute promyelocytic leukaemia (APL) is strongly correlated with obesity. APL is characterized by reciprocal translocation between chromosomes 15 and 17 resulting in the formation of the PML/RARα oncoprotein. However, the molecular mechanisms explaining the effects of obesity on APL development have not been elucidated. To recapitulate clinical observations, we characterized a mouse model of diet-induced obesity using transgenic mice constitutively expressing PML/RARα in the hematopoietic system (PML/RARα KI mice) and wild type mice as a control. Mice were fed standard diet (SD) or high fat diet (HFD), and leukaemia-free survival was monitored. We observed that HFD-fed PML/RARα KI mice developed leukaemia earlier and with higher penetrance than SD-fed mice. We evaluated the extent of DNA damage in hematopoietic stem cells (HSC) after four months of diet. We demonstrated that HFD-fed PML/RARα KI mice presented a 40% increase of DNA damage in HSCs as compared to SD-fed PML/RARα mice. However, this was not associated with an increased mutational load as revealed by whole genome sequencing-based method. We investigated whether HFD confers a proliferative advantage to PML/RARα bone marrow using colony forming assays. Indeed, we observed that HFD PML/RARα bone marrow has a higher clonogenicity than bone marrow from SD-fed mice. Finally, we demonstrated that linoleic acid (LA), which is the main component of HFD increases PML/RARα enhanced self-renewal.