Annual Report 2023

Team Yokoyama

Akihiko Yokoyama, Yosuke Komata, Tomoaki Fujii, Hagumu Sato, Ikuko Yokoyama, Ayako Yokoyama, Kanae Ito

Introduction

 Our focus is on molecular pathology of childhood cancers such as refractory leukemia.

The Team and What We Do

 Our team investigates the molecular mechanisms of leukemia and Wilms tumor using mouse disease models, proteomics approaches, and epigenome analytical tools. We aim to identify novel molecular targets for drug development by elucidating the molecular mechanisms by which oncoproteins cause aberrant self-renewal.

Research Activities

 We have revealed mechanisms by which oncoproteins cause aberrant self-renewal. We particularly focused on the functions of MOZ and MLL, both of which activate expression of the genes previously expressed in mother cells, thereby promoting self-renewal. This year, we reported that the MOZ/ENL complex plays a pivotal role in AF10-mutated leukemia. Based on our findings, we have proposed novel therapeutic targets for refractory leukemia. Moreover, a molecularly targeted drug which we developed by collaborating with a pharmaceutical company is now in clinical trials in North America and Japan.

1. Xiao M, Kondo S, Nomura M, Kato S, Nishimura K, Zhang W, Zhang Y, Akashi T, Viny A, Shigehiro T, Ikawa T, Yamazaki H, Fukumoto M, Tanaka A, Hayashi Y, Koike Y, Aoyama Y, Ito H, Nishikawa H, Kitamura T, Kanai A, Yokoyama A, Fujiwara T, Goyama S, Noguchi H, Lee SC, Toyoda A, Hinohara K, Abdel-Wahab O, Inoue D. BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state Nature Communications (2023) Dec 15;14(1):8372. doi: 10.1038/s41467-023-44081-6.

2. Chen Y, Yamamoto T, Takahashi Y, Moro T, Tajima T, Sakaguchi Y, Sakata N, Yokoyama A, Hijioka S, Sada A, Tabata Y, Ohki R. Metabolic intervention by low carbohydrate diet suppresses the onset and progression of neuroendocrine tumors Cell Death Disease (2023) Sep 7;14(9): 597. doi: 10.1038/s41419-023-06123-1.

3. #Komata Y, #Kanai A, Maeda T, Inaba T, *Yokoyama A MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins Nature Communications (2023)14:1979 https://doi.org/10.1038/s41467-023-37712-5

Clinical Trials

 A novel drug for leukemia that we developed with Sumitomo Pharma is now in the phase I/II clinical trial in Canada, the US, and Japan. Since we are a basic research team, we are not directly engaged in the clinical trials.

Education

 Training: Researchers and technicians

Future Prospects

 We aim to identify novel therapeutic targets, which may lead to development of new therapies, through the deep understanding of the molecular mechanisms of childhood cancer.