Annual Report 2020

Tsuruoka Metabolomics Laboratory (Team Yokoyama)

Akihiko Yokoyama, Hiroshi Okuda, Ryo Miyamoto, Satoshi Takahashi, Ayako Yokoyama, Kanae Ito

Introduction

 We focus on molecular pathology of childhood cancers such as leukemia.

The Team and What We Do

 Our team investigate the molecular mechanisms of leukemia using mouse disease models and epigenome analytical tools. We aim to elucidate the molecular mechanisms by which leukemic oncoproteins cause aberrant gene regulation and identify novel molecular targets for drug development.

Research activities

 Most of cancer cells express the MYC gene to promote proliferation. However, forced expression of MYC alone is insufficient to cause leukemia in mouse models, suggesting that additional factors are required for oncogenesis. We identified novel collaborative factors for MYC-mediated leukemogenesis. Moreover, we discovered that leukemic MLL oncoproteins physically associate with MYST family histone acetyltransferases such as MOZ and HBO1 to promote leukemogenesis. We also discovered that leukemic MOZ oncoproteins cause leukemic transformation using MLL-mediated transactivation system, suggesting that therapeutic strategies for MLL-rearranged leukemia can be applied to MOZ-rearranged leukemias.

Education

 We are training a graduate school student from Kyoto University.

Future Prospects

 Our research increases understanding of the molecular mechanisms of leukemia. Along the way, we will identify novel therapeutic targets, which may lead to development of new molecularly targeted therapies.

List of papers published in 2020

Journal

1. Nagamachi A, Kanai A, Nakamura M, Okuda H, Yokoyama A, Shinriki S, Matsui H, Inaba T Multi-organ failure with abnormal receptor metabolism in mice mimicking Samd9/9L syndromes J. Clin. Invest. 131(4):e140147. (2020) https://doi.org/10.1172/JCI140147.

2. 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 Reports 32:13;108200 (2020) doi.org/10.1016/j.celrep.2020.108200

3. Takeda R, Asada S, Park SJ, Yokoyama A, Becker H, Kanai A, Visconte V, Hershberger C, Hayashi Y, Yonezawa T, Tamura M, Fukushima T, Tanaka Y, Fukuyama T, Matsumoto A, Yamasaki S, Nakai K, Yamazaki S, Inaba T, Shibata T, Inoue D, Honda H, Goyama S, Maciejewski J, Kitamura T. HHEX promotes myeloid transformation in cooperation with mutant ASXL1 Blood 136 (14): 1670-1684. (2020) DOI:10.1182/blood-2019-126663

4. Ochi Y, Kon A, Sakata T, Nakagawa MM, Nakazawa N, Kakuta M, Kataoka K, Koseki H, Nakayama M, Morishita D, Tsuruyama T, Saiki R, Yoda A, Okuda R, Yoshizato T, Yoshida K, Shiozawa Y, Nannya Y, Kotani S, Kogure Y, Kakiuchi N, Nishimura T, Makishima H, Malcovati L, Yokoyama A, Takeuchi K, Sugihara E, Sato T, Sanada M, Takaori-Kondo A, Cazzola M, Kengaku M, Miyano S, Shirahige K, Suzuki H, Ogawa S. Combined Cohesin-Runx1 deficiency synergistically perturbs chromatin looping and causes myelodysplastic syndromes. Cancer Discovery 10:836-53 (2020) DOI: 10.1158/2159-8290.CD-19-0982

5. Takahashi S, *Yokoyama A. The molecular functions of common and atypical MLL fusion protein complexes BBA - Gene Regulatory Mechanisms 1863(7):194548 (2020) doi: 10.1016/j.bbagrm.2020.194548