American Association for Cancer Research
15357163mct170580-sup-185207_3_supp_4345227_tyhy6f.pdf (719.87 kB)

Supplementary Tables 1-3, Figures 1-3, and Supplementary Materials and Methods from Pharmacologic Inhibition of the Menin–MLL Interaction Leads to Transcriptional Repression of PEG10 and Blocks Hepatocellular Carcinoma

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journal contribution
posted on 2023-04-03, 15:07 authored by Katarzyna Kempinska, Bhavna Malik, Dmitry Borkin, Szymon Klossowski, Shirish Shukla, Hongzhi Miao, Jingya Wang, Tomasz Cierpicki, Jolanta Grembecka

Supplementary Figure 1. Expression of menin, MLL1 and MLL2 in HCC cell lines; Supplementary Figure 2. MI-503 affects cell migration in HCC cell lines; Supplementary Figure 3. MI-503 does not induce toxicity in mice; Supplementary Table 1. Inhibition of cell viability in HCC cell lines by menin-MLL inhibitors; Supplementary Table 2. RNAseq data from MI-503 treatment in HepG2 cells; Supplementary Table 3. Mutation status of CTNNB1 in human HCC cell lines


University of Michigan




Hepatocellular carcinoma (HCC) accounts for approximately 85% of malignant liver tumors and results in 600,000 deaths each year, emphasizing the need for new therapies. Upregulation of menin was reported in HCC patients and high levels of menin correlate with poor patient prognosis. The protein–protein interaction between menin and histone methyltransferase mixed lineage leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients. Here, we demonstrate that the menin–MLL inhibitor MI-503 shows antitumor activity in in vitro and in vivo models of HCC and reveals the potential mechanism of menin contribution to HCC. Treatment with MI-503 selectively kills various HCC cell lines and this effect is significantly enhanced by a combination of MI-503 with sorafenib, the standard-of-care therapy for HCC. Furthermore, MI-503 reduces sphere formation and cell migration in in vitro HCC models. When applied in vivo, MI-503 gives a strong antitumor effect both as a single agent and in combination with sorafenib in mice xenograft models of HCC. Mechanistically, treatment with MI-503 downregulates expression of several genes known to play a critical role in proliferation and migration of HCC cells, including PEG10, and displaces the menin–MLL1 complex from the PEG10 promoter, resulting in reduced H3K4 methylation and transcriptional repression. Overall, our studies reveal a mechanistic link between menin and genes involved in HCC and demonstrate that pharmacologic inhibition of the menin–MLL interaction might represent a promising therapeutic approach for HCC. Mol Cancer Ther; 17(1); 26–38. ©2017 AACR.

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