Abstract 1637: ATP-citrate lyase transgenic mice frequently develop lymphoma/leukemia spontaneously

Abstract

Abstract ATP-citrate lyase (ACLY) catalyzes the generation of acetyl-CoA from citrate. ACLY expression is upregulated and/or ACLY is phosphorylated in several types of cancer. We generated ACLY transgenic mice (Tg) to examine the role of ACLY in carcinogenesis. (Materials and methods) Using human ACLY cDNA under the ROSA26 promoter, Tg with a C57BL background was established. We observed the Tg without treatment. Statistical analyses were performed using the Chi-square and Fisher's exact test. (Results) Of 24 male (M) Tg, aged 24–30 months, 14 (58%), 7 (29%), and 1 (4%) spontaneously developed lymphoma/leukemia (LL), lung carcinoma (LC), and small intestinal carcinoma (SIC), respectively. Since some C57BL mouse colonies are genetically susceptible to LL, and we have previously examined human cases of carcinoma, the Tg were back-crossed with C3H mice, which are resistant to LL and susceptible to carcinoma, especially hepatocellular carcinoma (HCC). A total of 129 (M: 67, female (F): 62) Tg were observed for 18 months. Forty-nine C3H mice (M: 19, F: 30) from the same colony were used as controls. Multiple tumors were counted individually. Seventy-three Tg (57%; M: 41, 61%; F: 32, 52%) and 8 controls (16%; M: 4, 21%; F: 4, 13%) developed cancer. The Tg developed significantly more tumors (total (T), M, F: all p<0.05), including 33 HCC (26%; M: 22, 33%; F: 11, 18%), 28 LL (22%; M: 12, 18%; F: 16, 26%), 7 LC (5%; M: 6, 9%; F: 1, 2%), 4 sarcomas (Sa)(3%; M: 2, 3%; F: 2, 3%), 2 SIC (2%; M: 2, 3%; F: 0), 2 skin appendage carcinomas (SAC) (2%; M: 0; F: 2, 3%), and 1 ovarian cancer (Ov) (1%; F: 1, 2%), than the control mice, which developed 7 HCC (14%; M: 4, 21%; F: 3, 10%), 1 LC (2%; M: 1, 5%; F: 0), and 1 Ov (2%; F: 1, 3%). No LL was seen in the controls. The frequency of HCC did not differ significantly between the Tg and controls (T, M, F: all p>0.05). (Discussion) ACLY was reported to be related to the carcinogenesis of anaplastic large cell lymphoma (Basappa J. et al. Blood 2015 126:465). This study suggests that ACLY might contribute to LL development. Table:Summary of developed cancersNumberTotal cancerHCCLLLCSICSaSACOvACLY12973(57%)*33(26%)28(22%)7(5%)2(2%)4(3%)2(2%)1(1%)Male6741(61%)**22(33%)12(18%)6(9%)2(3%)2(3%)0-Female6232(52%)***11(18%)16(26%)1(2%)02(3%)2(3%)1(2%)Control498(16%)*7(14%)01(2%)0001(2%)Male194(21%)**4(21%)01(5%)000-Female304(13%)***3(10%)000001(3%)*, **, ***; p<0.05 Citation Format: Hiroaki Kanda, Kimie Nomura, Toshihiko Iizuka, Mutsunori Fujiwara, Yuichi Ishikawa, Toshiro Migita. ATP-citrate lyase transgenic mice frequently develop lymphoma/leukemia spontaneously [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1637.