Abstract 450: Obesity favours leukemogenesis through enhanced preleukemic stem cell self renewal via polyunsaturated fatty acid-dependent ER stress relief
Authors: Mazzarella Luca , Falvo Paolo , Sanarico Annagiulia , Gatti Elena , Pelicci Piergiuseppe 
Published: August 2018

Abstract
Obesity increases risk for multiple tumors, but impact on leukemia and its underlying molecular mechanism are poorly understood. Studies from our group and others showed that risk and outcome of Acute Promyelocytic Leukemia (APL) are more strongly associated with obesity than other hematological neoplasms. Intriguingly, in 2 independent cohorts (Italian and TCGA), obesity was associated with ~4 fold higher incidence of internal tandem duplications of the leukemogenic kinase FLT3 (FLT3-ITD), the first example of obesity-associated genetic alterations in cancer (unpublished). Here we propose a molecular mechanisms underlying obesity-associated leukemogenesis through our studies in murine models. Exposure to High fat Diet (HFD), an established model of obesity-related pathology, strongly accelerated disease onset and mortality in 3 murine models of hematological cancer: PML-RARa knockin (PRKI), developing an APL-mimicking disease; FLT3ITD knockin (FIKI) developing myeloproliferation; a new double PRKI-FIKI knockin mouse, developing APL-like disease but, surprisingly, with delayed latency compared to PRKI, presumably due to the known exhaustion of hematopoietic stem cells (HSC) associated with FLT3ITD. Preleukemic HSCs from HFD PRKI mice showed increased DNA damage in Comet assays, but surprisingly this was not associated with increased mutational load as revealed by a novel whole genome sequencing-based method. Instead, HSCs derived from HFD PRKI mice showed enhanced self-renewal in in vitro replating assays. Similarly, in the FIKI model we observed enhanced engraftment in serial competitive transplantation experiments in HFD-fed recipients. Delving more deeply in the molecular mechanisms, through bioinformatic analysis of RNAseq data from the TCGA we found upregulation of the linoleic acid (LA) pathway in obese APL patients. LA is the richest fatty acid in HFD and in many western diets, thus a likely candidate for mediating HFD activity. LA significantly enhanced PRKI serial replating efficiency; this was abolished by pharmacologically blocking LA metabolism through a 5-lipoxygenase inhibitor or its transcriptional effects through a PPARd inhibitor. In the FIKI model and in a FLT3ITD-inducible cell line, we revealed a previously unappreciated induction of ER stress by FLT3ITD, likely to underlie FLT3ITD-induced HSC exhaustion. HFD (in vivo) and LA (in vitro) relieved FLT3ITD-induced ER stress, as revealed by the attenuation of markers of adaptive response to ER stress (Unfolded Protein Response and RNA IRE1-dependent RNA decay). In conclusion, our study suggests a novel and somewhat counterinuitive model for obesity-associated cancerogenesis: rather than inducing cellular stress, HFD-induced obesity enhances the self-renewal of preleukemic stem cells through LA-mediated alleviation of oncogene-induced proteotoxic stress
Citation Format: Luca Mazzarella, Paolo Falvo, Annagiulia Sanarico, Elena Gatti, Piergiuseppe Pelicci. Obesity favours leukemogenesis through enhanced preleukemic stem cell self renewal via polyunsaturated fatty acid-dependent ER stress relief [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 450.