Annual Report 2017

Issay Kitabayashi, Kazutsune Yamagata, Takuo Katsumoto, Yutaka Shima, Yoko Ogawara, Emi Takamatsu, Yuuki Kagiyama, Shuhei Fujita, Makoto Nakagawa, Yukiko Aikawa, Tomoko Shoji

Introduction

 Acute myeloid 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 AML patients have a relapse and only 25-30% of young adults and fewer than 10% of older patients survive longer than five years, suggesting the presence of AML stem cells that are resistant to chemotherapy. Thus, AML stem cell eradication is thought to be crucial for the cure of AML. AML relapse after conventional chemotherapy is caused by a remaining population of drug-

resistant LSCs. Selective targeting of the chemo-

resistant population is a promising strategy for preventing and treating AML relapse.

Our team and what we do

 Our research purpose is to establish new therapeutic methods by identifying molecular targets that are essential for maintenance of hematological malignancy, especially AML stem cells.

Research activities

 Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 to maintain the stemness of LSCs. Here, we show that quiescent LSCs expressed the highest levels of enhancer of zeste (EZH) 1 and EZH2, the PRC2 catalytic subunits, in the AML hierarchy, and that dual inactivation of EZH1/2 eradicated quiescent LSCs to cure AML. Genetic deletion of Ezh1/2 in a mouse AML model induced cell cycle progression of quiescent LSCs and differentiation to LSCs, eventually eradicating AML LSCs. Quiescent LSCs showed PRC2-mediated suppression of Cyclin D, and Cyclin D-overexpressing AML was more sensitive to chemotherapy. We have developed a novel EZH1/2 dual inhibitor with a potent inhibitory activity against both EZH1/2. In AML mouse models and patient-derived xenograft models, the inhibitor reduced the number of LSCs, impaired leukemia progression, and prolonged survival. Taken together, these results show that dual inhibition of EZH1/2 is an effective strategy for eliminating AML LSCs.

 In a mouse model of AML expressing the MOZ-TIF2 fusion, we found that Ring1A and Ring1B, components of Polycomb repressive complex 1, play crucial roles in maintaining AML stem cells. The deletion of Ring1A and Ring1B (Ring1A/B) from MOZ-TIF2 AML cells diminished 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. Thus, Ring1A/B regulates and maintains AML stem cells in part 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.

Clinical trials

 First- in human clinical trials for EZH1/2 dual inhibitor have been started at the National Cancer Center Hospital (NCCH) and others.

Education

 Four post-doctoral fellows were trained for the research.

Future prospects

 On the basis of our research, we are developing anti-cancer drugs for patients with hematological malignancy.