Annual Report 2021
Division of Hematological Malignancy
Issay Kitabayashi, Kazutsune Yamagata, Takuo Katsumoto, Yutaka Shima, Haruka Shinohara, Junpei Ito, Yoko Kuroki, Yukiko Aikawa, Tomoko Shoji, Kimiharu Tauchi
Introduction
Acute myelogenous leukemia (AML) is the most common leukemia in Japan and the U.S. With current standard chemotherapy, approximately 70% of adults with AML can be expected to attain complete remission status following appropriate induction therapy. However, many of the patients suffer a relapse of AML and only 25-30% of young adults and fewer than 10% of older patients survive longer than 5 years, suggesting presence of AML stem cells that are resistant to chemotherapy. Thus, AML stem cell eradication is thought to be crucial for curing AML. AML relapse after conventional chemotherapy is caused by a remaining population of drug-resistant AML stem cells. Selective targeting of the chemo-resistant population is a promising strategy for preventing and treating AML relapse.
The Team and What We Do
Our research purpose involves establishing new therapeutic methods by identifying molecular targets that are essential for maintaining hematological malignancies, especially AML stem cells.
Research activities
Monocytic leukemia zinc finger protein (MOZ, MYST3, or KAT6A) is a MYST-type acetyltransferase involved in chromosomal translocation in AML and myelodysplastic syndrome. MOZ has been established to be essential for hematopoiesis; however, the role of MOZ in AML has not been addressed. We propose that MOZ is critical for AML development induced by MLL-AF9, MLL-AF10, or MOZ-TIF2 fusions. MOZ-deficient hematopoietic stem/progenitor cells (HSPCs) transduced with an MLL-AF10 fusion gene neither formed colonies in methylcellulose nor induced AML in mice, and MOZ-deficient HSPCs bearing MLL-AF9 also generated significantly reduced colony and cell numbers. MOZ-deficient HSPCs expressing MOZ-TIF2 could form colonies in vitro but could not induce AML in mice. By contrast, MOZ was dispensable for colony formation by HOXA9-transduced cells and AML development caused by HOXA9 and MEIS1, suggesting a specific requirement for MOZ in AML induced by MOZ/MLL-fusions. Expression of the HOXA9 and MEIS1 genes was decreased in MOZ-deficient MLL-fusion expressing cells, while expression of MEIS1, but not HOXA9, was reduced in MOZ-deficient MOZ-TIF2 AML cells. AML development induced by MOZ-TIF2 was rescued by introducing MEIS1 into MOZ-deficient cells carrying MOZ-TIF2. MEIS1 deletion impaired MOZ-TIF2¬-mediated AML development. MOZ-TIF2 and endogenous MOZ binding and active histone modifications were also severely reduced at the MEIS1 locus in MOZ-deficient MOZ-TIF2 and MLL-AF9 AML cells. These results suggest that endogenous MOZ is critical for MOZ/MLL-fusion-induced AML development and maintains fusion binding and active chromatin signatures at target gene loci.
Malignant rhabdoid tumors (MRTs) are rare and highly aggressive pediatric cancers with no standard of care. MRTs are characterized by loss of SMARCB1, which results in upregulated expression of enhancer of zeste homolog 2 (EZH2), which is responsible for the methylation of lysine 27 of histone H3 (H3K27me3), leading to the repression of gene expression. Although previous reports suggest EZH2 as an effective therapeutic target, the functions of EZH1, the other homolog of EZH, in MRT remain unknown. Here, we show that EZH1, as well as EZH2, contributes to MRT cell growth and H3K27 methylation. Depletion or selective inhibition of EZH2 led to a compensatory increase in EZH1 expression, and depletion of EZH1 enhanced the effect of EZH2 inhibition. EZH1/2 dual inhibitors suppressed MRT cell growth markedly, reflecting the reduction of H3K27me3 accumulation at one of the EZH1/2 targets, the CDKN2A locus. Dual inhibition of EZH1/2 in vivo suppressed tumor growth completely, with no significant adverse effects. These findings indicate that both EZH1 and EZH2 are potential targets for MRT therapy, and that EZH1/2 dual inhibitors may be promising therapeutic strategies for MRT.
Clinical trials
Phase II clinical trials of the mIDH1 inhibitor and EZH1/2 dual inhibitor are ongoing at the National Cancer Center Hospital and elsewhere. A phase I clinical trial of the MLL/NEMIN inhibitor is ongoing at the National Cancer Center Hospital and elsewhere.
Education
One post-doctoral fellow and two graduate students were trained for research.
Future Prospects
Based on our research, we are developing anti-cancer therapies for cancer patients.
List of papers published in 2021
Journal
1. Kagiyama Y, Fujita S, Shima Y, Yamagata K, Katsumoto T, Nakagawa M, Honma D, Adachi N, Araki K, Kato A, Inaki K, Ono Y, Fukuhara S, Kobayashi Y, Tobinai K, Kitabayashi I. CDKN1C-mediated growth inhibition by an EZH1/2 dual inhibitor overcomes resistance of mantle cell lymphoma to ibrutinib. Cancer science, 112:2314-2324, 2021
2. Yamagata K, Shino M, Aikawa Y, Fujita S, Kitabayashi I. Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia. Leukemia, 35:2840-2853, 2021
3. Kishimoto K, Kanazawa K, Nomura M, Tanaka T, Shigemoto-Kuroda T, Fukui K, Miura K, Kurosawa K, Kawai M, Kato H, Terasaki K, Sakamoto Y, Yamashita Y, Sato I, Tanuma N, Tamai K, Kitabayashi I, Matsuura K, Watanabe T, Yasuda J, Tsuji H, Shima H. Ppp6c deficiency accelerates K-ras(G12D) -induced tongue carcinogenesis. Cancer medicine, 10:4451-4464, 2021
4. Nakagawa M, Sekimizu M, Endo M, Kobayashi E, Iwata S, Fukushima S, Yoshida A, Kitabayashi I, Ichikawa H, Kawai A, Nakatani F. Prognostic impact of IDH mutations in chondrosarcoma. Journal of orthopaedic science: official journal of the Japanese Orthopaedic Association, 2021
5. Takeuchi Y, Kimura N, Murayama T, Machida Y, Iejima D, Nishimura T, Terashima M, Wang Y, Li M, Sakamoto R, Yamamoto M, Itano N, Inoue Y, Ito M, Yoshida N, Inoue JI, Akashi K, Saya H, Fujita K, Kuroda M, Kitabayashi I, Voon D, Suzuki T, Tojo A, Gotoh N. The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America, 118:2021