Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia, has recently been identified as an obesity-associated cancer (OAC) (1). Obesity has, in fact, been clearly linked to increased risk of multiple malignancies and worse outcomes for patients with these OACs (2). Murine models for solid tumors have been useful to better understand and disrupt the obesity-cancer linkage (3-10); however, no animal model of APL has been evaluated for the effect of obesity on disease development, penetrance, or latency. The goal of this research was to interrogate and characterize the impact of obesity on the development of APL so as to provide a murine model for future

Aim: Obesity and obesogenic diets might partly accelerate cancer development through epigenetic mechanisms.To determine these early effects, we investigated the impact of three days of a high-fat diet on epigenomic and transcriptomic changes in Apc Min /+ murine intestinal epithelia.Method: ChIP-Seq and RNA-Seq were performed on small intestinal epithelia of WT and Apc Min /+ male mice fed high-fat diet (HFD) or low-fat diet (LFD) for three days to identify genomic regions associated with differential H3K27ac levels as a marker of variant enhancer loci (VELs) as well as differentially expressed genes (DEGs).Results: Regarding epigenetic and transcriptomic changes, diet type (LFD vs. HFD) showed a significant impact, and genotype (WT vs. Apc Min/+ ) showed a small impact. Compared to LFD, HFD resulted in 1306 gained VELs, 230 lost VELs, 133 upregulated genes, and 127 downregulated genes in WT mice, with 1056 gained VELs, 371 lost VELs, 222 upregulated genes, and 182 downregulated genes in Apc Min/+ mice. Compared to the WT genotype, the Apc Min/+ genotype resulted in zero changed VELs for either diet type group, 21 DEGs for LFD, and 48 DEGs for HFD. Most gained VELs, and upregulated genes were associated with lipid metabolic processes. Gained VELs were

Hepatocellular Carcinoma (HCC) is the 5th most common cancer worldwide, with increased risk occurring in patients with hepatitis C and B, alcoholism, aflatoxin, and metabolic diseases. Animal models that target liver cells with chemical, physical or biological agents are useful for understanding molecular pathways, but do not capture the natural development of liver cancer through gene-environment interactions. By contrast, several inbred strains of mice have been used to study these interactions in diet-induced metabolic diseases. In particular, C57BL/6J (B6) inbred mice are susceptible to diet-induced obesity, lipid disorders and insulin resistance, whereas A/J mice produce no signs of these diet-induced conditions. In these inbred models, the action of many genes and gene-environment interactions more closely reflect the usual features in non-alcoholic steatohepatitis (NASH) and HCC pathogenesis. Previous studies showed that B6 males are susceptible to diet-induced obesity and non-alcoholic fatty liver disease (NAFLD). We therefore examined the long-term effects of a high fat (HF) diet versus a low fat (LF) diet in males from two inbred strains A/J and B6 to determine whether conditions associated with risk factors ultimately transition to HCC. On the HF diet, A/J males remained lean and were resistant to NASH, whereas B6 males were obese and showed histological and biochemical features of NASH, and in many cases NASH progressed to HCCs with molecular and histological features that were remarkably similar to those reported for the two major HCC classes in humans. On the LF diet, both A/J and B6 were resistant to NASH and HCC. Messenger RNA profiles of HCCs versus tumor-free livers implicated two signaling networks, one centered on Myc and the other on NFκB. Also, we tested whether long-term exposure to the HF diet would give the same response in Chromosome Substitution Strains (CSSs) as with the parental strains. The B6-ChrA/J CSS panel consists of 22 mouse strains in which each CSS consist of a single substituted chromosome from a donor strain (A/J) onto the background of a host strain (B6). We found that most CSSs were resistant to diet-induced obesity, matching their A/J parent, with a few resembling the obesity of the B6 parental strain. We selected two strains from the CSS panel, B6-Chr18A/J which shows diet-induced obesity, and B6-Chr5A/J, an obesity resistant strain, to test long-term HF diet effects. Although initially lean during short-term HF diet tests, B6-Chr5A/J eventually became obese and showed a strong susceptibility to NASH and HCC. By contrast, B6-Chr18A/J remained obese throughout the long-term study, but remarkably maintained features of a normal liver, showed a greatly reduced susceptibility to NASH, and complete resistance to HCC. These studies show that complex interactions between genetic and dietary factors modulate susceptibility to liver disease and cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2413. doi:10.1158/1538-7445.AM2011-2413

While a number of solid tumors are identified as obesity-associated cancers, multiple myeloma and acute promyelocytic leukemia (APL) are the only hematologic malignancies included in this category. APL is a highly treatable form of AML characterized by maturation arrest at the promyelocyte stage, and frequent cures with combined ATRA and Arsenic Trioxide therapy. APL is initiated by a chromosomal translocation that causes the fusion of thePMLandRARAgenes, leading to the production of PML-RARA protein. To determine if obesity accelerates the development of APL, we used a genetically-engineered knock-in model in which human PML-RARA cDNA was inserted into the 5' untranslated region of the murine cathepsin G gene (Ctsg), which targets expression to early myeloid progenitor cells. This knock-in transgene was extensively backcrossed (>20 generations) into the C57BL/6J (B6) genetic background, which has been consistently shown to render mice susceptible to diet-induced obesity.Ctsg-PML-RARA mice developed on the B6 background generate a lethal APL-like leukemia with a latency of 8-12 months, and a penetrance of about 60%, as cooperating mutations occur and cause clinical disease. We placed cohorts of B6.Ctsg-PML-RARA heterozygous (mCG+/PR) and wild-type (WT) mice, genotyped by PCR, on high-fat (HFD) [57% coconut oil fat] and low-fat (LFD) [10% coconut oil fat] diets, collecting peripheral blood via the retro- orbital sinus at 30 day intervals and performing automated blood counts to observe temporal associations in disease development. HFD feeding significantly accelerated the development of APL in mCG+/PR mice, leading to anemia, thrombocytopenia, leukocytosis of the granulocyte series, and splenomegaly. Survival rate reduction demonstrated sexual-dimorphism, with male HFD-fed mCG+/PR mice displaying a median leukemia-free survival time of 211 days compared to 266 days in the female HFD-fed mCG+/PR cohort. In contrast, LFD-fed mCG+/PR male mice showed a median survival time of 318 days, whereas none of LFD-fed mCG+/PR female group nor any of the WT groups on HFD or LFD have reached median survival as of 325 days. Moreover, no signs of leukemia were observed in either HFD- and LFD-fed WT groups, indicating that adiposity alone had no leukemogenic effect. These studies clearly demonstrate that obesity accelerates leukemogenesis in theCtsg-PML-RARA mouse model of acute promyelocytic leukemia. High density flow cytometry will be applied in the bone marrow of the different groups to evaluate the modulation of multiple hematopoietic cell lineages and cell surface markers. Disclosures No relevant conflicts of interest to declare.