Annual Report 2021
Tsuruoka Metabolomics Laboratory (Team Makinoshima)
Akihiko Yokoyama, Yosuke Komata, Hagumu Sato, Ikuko Yokoyama, 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 and Wilms tumor using mouse disease models and epigenome analytical tools. We aim to elucidate the molecular mechanisms by which oncoproteins cause aberrant gene regulation and identify novel molecular targets for drug development.
Research activities
Most 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 HOXA9 as a novel collaborative factor for MYC-mediated leukemogenesis. Moreover, we discovered that leukemic MLL oncoproteins physically associate with HBO1 histone acetyltransferase to promote leukemogenesis. With these newly acquired mechanistic insights, we are developing novel molecularly targeted drugs for refractory leukemia.
1. *Yokoyama A. Role of the MOZ/MLL-mediated transcriptional activation system for self-renewal in normal hematopoiesis and leukemogenesis. The FEBS Journal (REVIEW) (2021) doi:10.1111/febs.16180
2. Yamamoto K, Goyama S, Asada S, Fujino T, Yonezawa T, Sato N, Takeda R, Tsuchiya A, Fukuyama T, Tanaka Y, Yokoyama A, Toya H, Kon A, Nannya Y, Onoguchi-Mizutani R, Nakagawa S, Hirose T, Ogawa S, Akimitsu N, Kitamura T. A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells. Cell Reports 36(8):109576. (2021) doi: 10.1016/j.celrep.2021.109576.
3. Takahashi S, Kanai A, Okuda H, Miyamoto R, Komata Y, Kawamura T, Matsui H, Inaba T, Takaori-Kondo A, *Yokoyama A. HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis. eLife 10:e65872 (2021) DOI: https://doi.org/10.7554/eLife.65872
4. Capodanno Y, Chen Y, Schrader J, Tomosugi M, Sumi S, Yokoyama A, Hiraoka N, Ohki R. Cross-talk among MEN1, p53 and Notch regulates the proliferation of pancreatic neuroendocrine tumor cells by modulating INSM1 expression and subcellular localization Neoplasia 23(9):979-992. (2021) doi: 10.1016/j.neo.2021.07.008
5. *Yokoyama A. Leukemogenesis via aberrant self-renewal by the MLL/AEP-mediated transcriptional activation system. Cancer Science (REVIEW) (2021) https://doi.org/10.1111/cas.15054
6. Miyamoto R, Kanai A, Okuda H, Komata Y, Takahashi S, Matsui H, Inaba T, *Yokoyama A. HOXA9 promotes MYC-mediated leukemogenesis by maintaining gene expression for multiple anti-apoptotic pathways. eLife 10:e64148 (2021) DOI: https://doi.org/10.7554/eLife.64148
7. Miyamoto R, Yokoyama A. Protocol for fractionation-assisted native ChIP (fanChIP) to capture protein-protein/DNA interactions on chromatin. STAR Protocols 2, 100404 (2021) doi: https://doi.org/10.1016/j.xpro.2021.100404
Clinical trials
A novel drug for leukemia that we developed with Sumitomo Pharma is now in the phase I clinical trial in Canada, the US, and Japan.
Education
A graduate student from Kyoto University obtained his doctoral degree.
Future Prospects
Our research aims to understand the molecular mechanisms of childhood cancer. Along the way, we will identify novel therapeutic targets, which may lead to development of new molecularly targeted therapies.