Annual Report 2020
Division of Hematological Malignancy
Issay Kitabayashi, Kazutsune Yamagata, Takuo Katsumoto, Yutaka Shima, Haruka Shinohara, Junpei Ito, Rie Sawado, Yukiko Aikawa, Tomoko Shoji
The Team and What We Do
Our research purpose is to establish new therapeutic methods by identifying molecular targets that are essential for maintaining hematological malignancy, especially AML stems.
Research activities
Chromosome translocations involving the MLL gene are common rearrangements in leukemia. Such translocations fuse the MLL 5’-region to partner genes in frame, producing MLL fusions that cause MLL-related leukemia. MLL fusions activate the transcription of target genes such as the HoxA cluster and Meis1; however, the underlying mechanisms remain to be fully elucidated. In this study, we discovered that Tip60, a MYST-type histone acetyltransferase, was required for the expression of the HoxA cluster and Meis1 genes and the development of MLL-fusion leukemia. Tip60 was recruited by MLL-AF10 and MLL-ENL fusions to the Hoxa9 locus, where it acetylated H2A.Z, thereby promoting Hoxa9 gene expression. Conditional deletion of Tip60 prevented the development of MLL-AF10 and MLL-ENL leukemia, indicating that Tip60 is indispensable for the leukemogenic activity of the MLL-AF10 and MLL-ENL-fusions. Our findings provide novel insight about epigenetic regulation in the development of MLL-AF10 and MLL-ENL-fusion leukemia.
Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma, which is characterized by overexpression of cyclin D1. Although novel drugs, such as ibrutinib, show promising clinical outcomes, relapsed MCL often acquires drug resistance. Therefore, alternative approaches for refractory and relapsed MCL are needed. We examined whether a novel inhibitor of enhancer of zeste homologs 1 and 2 (EZH1/2), OR-S1 (a close analog of the clinical-stage compound valemetostat), had an antitumor effect on MCL cells. In an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model, OR-S1 treatment by oral administration significantly inhibited MCL tumor growth, whereas ibrutinib did not. In vitro growth assays showed that compared with an established EZH2-specific inhibitor GSK126, OR-S1 had a marked antitumor effect on MCL cell lines. Furthermore, comprehensive gene expression analysis was performed using OR-S1-sensitive or insensitive MCL cell lines and showed that OR-S1 treatment modulated B-cell activation, differentiation, and cell cycle. In addition, we identified Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, also known as p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation. These results suggest that EZH1/2 may be a potential novel target for trating aggressive ibrutinib-resistant MCL via CDKN1C-mediated cell cycle arrest.
Clinical trials
Phase II clinical trials for mIDH1 inhibitor and EZH1/2 dual inhibitor are ongoing at the National Cancer Center Hospital and others.
Education
A post-doctoral fellow and a graduate student were trained for research.
Future Prospects
Based on our research, we are developing anti-cancer therapies for cancer patients.
List of papers published in 2020
Journal
1. Machida Y, Nakagawa M, Matsunaga H, Yamaguchi M, Ogawara Y, Shima Y, Yamagata K, Katsumoto T, Hattori A, Itoh M, Seki T, Nishiya Y, Nakamura K, Suzuki K, Imaoka T, Baba D, Suzuki M, Sampetrean O, Saya H, Ichimura K, Kitabayashi I. A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model. Mol Cancer Ther, 19:375-383, 2020
2. Fujiwara N, Shibutani S, Sakai Y, Watanabe T, Kitabayashi I, Oshima H, Oshima M, Hoshida H, Akada R, Usui T, Ohama T, Sato K. Autophagy regulates levels of tumor suppressor enzyme protein phosphatase 6. Cancer Sci, 111:4371-4380, 2020
3. Miyamoto R, Okuda H, Kanai A, Takahashi S, Kawamura T, Matsui H, Kitamura T, Kitabayashi I, Inaba T, Yokoyama A. Activation of CpG-Rich Promoters Mediated by MLL Drives MOZ-Rearranged Leukemia. Cell Rep, 32:108200, 2020