Annual Report 2018
Division of Hematological Malignancy
Issay Kitabayashi, Kazutsune Yamagata, Takuo Katsumoto, Yoko Ogawara, Ayuna Httori, Haruka Shinohara, Makoto Nakagawa, Yukiko Aikawa, Tomoko Shoji
Introduction
AML is the most common form of leukemia in Japan and the U.S. With current standard chemotherapy, complete remission can be expected in around 70% of adult AML patients following appropriate induction therapy. However, many such patients relapse into AML and only 25-30% of young adults and fewer than 10% of older patients survive beyond five years, suggesting the presence of AML stem cells resistant to chemotheraphy. Accordingly, eradicating AML stem cells is considered crucial to cure AML. AML relapse after conventional chemotherapy is caused by a remaining population of drug-resistant LSCs and selectively targeting the chemo-resistant population is considered 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 stems.
Research activities
In an AML mouse model expressing MOZTIF2 fusion, we found that Ring1A and Ring1B, components of Polycomb repressive complex 1, play crucial roles in maintaining AML stem cells. Deleting Ring1A and Ring1B (Ring1A/B) from MOZ-TIF2 AML cells diminished the self-renewal capacity and induced the expression of numerous genes, including Glis2. Overexpression of Glis2 caused MOZ-TIF2 AML cells to differentiate into mature cells, whereas Glis2 knockdown in Ring1A/B-deficient MOZ-TIF2 cells inhibited differentiation. Accordingly, Ring1A/B regulates and maintains AML stem cells; partially by repressing Glis2 expression, which promotes their differentiation. These findings provide new insights into the mechanism of AML stem cell homeostasis and reveal novel targets for cancer stem cell therapy.
Multiple myeloma (MM) is an incurable hematological malignancy caused by the accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of the remaining population of drug-resistant myeloma stem cells. Sidepopulation (SP) cells show cancer stem cell-like characteristics in MM, which is why targeting such cells represents a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that both EZH1 and EZH2 help maintain the stems of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in-vitro and in-vivo, including a unique patient-derived xenograft model. Moreover, long-term continuous dosing of OR-S1 completely cured mice-bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM and overactivation of this signaling induced by the dual inhibition of EZH1/2 eradicated myeloma stem cells and adversely affected tumorigenesis, suggesting that the repression of WNT signaling by PRC2 is key to maintaining MM cell stems. Our results show the role of EZH1/2 in maintaining myeloma stem cells and provide a preclinical rationale to apply OR-S1 therapeutically, heralding significant advances in MM treatment.
Clinical trials
The first in-human clinical trials for the EZH1/2 dual inhibitor are ongoing at the National Cancer Center Hospital and elsewhere.
Education
Four post-doctoral fellows were trained for research.
Future prospects
Based on our research, we are developing anti-cancer drugs for patients with hematological malignancies.
List of papers published in 2018
Journal
1. Tanaka M, Ishige A, Yaguchi M, Matsumoto T, Shirouzu M, Yokoyama S, Ishikawa F, Kitabayashi I, Takemori T, Harada M. Development of a simple new flow cytometric antibody-dependent cellular cytotoxicity (ADCC) assay with excellent sensitivity. J Immunol Methods, 464:74-86, 2019
2. Nakagawa M, Fujita S, Katsumoto T, Yamagata K, Ogawara Y, Hattori A, Kagiyama Y, Honma D, Araki K, Inoue T, Kato A, Inaki K, Wada C, Ono Y, Yamamoto M, Miura O, Nakashima Y, Kitabayashi I. Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma. Cancer Sci, 110:194-208, 2019
3. Nakagawa M, Kitabayashi I. Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies. Cancer Sci, 109:2342-2348, 2018
4. Ikawa Y, Nishimura R, Maeba H, Fujiki T, Kuroda R, Noguchi K, Fukuda M, Mase S, Araki R, Mitani Y, Sato T, Terui K, Ito E, Kitabayashi I, Yachie A. Deep spontaneous molecular remission in a patient with congenital acute myeloid leukemia expressing a novel MOZ-p300 fusion transcript. Leuk Lymphoma, 59:2497- 2499, 2018
5. Shima H, Takamatsu-Ichihara E, Shino M, Yamagata K, Katsumoto T, Aikawa Y, Fujita S, Koseki H, Kitabayashi I. Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells. Blood, 131:1833-1845, 2018
6. Fujita S, Honma D, Adachi N, Araki K, Takamatsu E, Katsumoto T, Yamagata K, Akashi K, Aoyama K, Iwama A, Kitabayashi I. Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia. Leukemia, 32:855-864, 2018