Molecular mechanisms of blood cancer and clonal hematopoiesis-related cardiovascular disease

Abstract

Blood cancers such as leukemia and lymphoma demand invention of novel drugs as operational removal of cancer lessons is not an option. Recently, driver mutations for blood cancer and its relavant cancer predisposition and clonal hematopoiesis, which is considered to a pre-cancer state of blood cancer have been identified and more comprehensively catalogued. The clonal hematopoiesis occurs in elderlies and triggers not only blood cancer but also cardiovascular disease. Although the information about the driver mutations is accumulating, the understanding of the molecular mechanisms of disease caused by these mutations and subsequent drug development are not moving forward as quickly. In order to facilitate the development of novel therapies, we set out to build a team among the JH institutions to speed up the process from the understanding of the mutations as the origin of the disease to understanding the molecular mechanisms of the disease and development of novel therapies.

In this research group, we analyze the genome of the whole age spectrum from newborns to elderlies. We aim to identify novel driver mutations not only by analyzing the existing database but also by analyzing new patient samples with blood cancer and healthy individuals who potentially have clonal hematopoiesis. We aim do develop animal disease models to study the molecular mechanisms of disease onset. Using the animal models, we try to develop novel drugs. In this research proposal, we will discover novel driver mutations, improve the understanding of the disease mechanisms, and promote drug development for blood cancer and clonal hematopoiesis-related cardiovascular disease.

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Perspectives

We hope to gain knowledge about the genomic alterations regarding blood cancer and clonal hematopoieis. By teaming up among NCCHD, NCC, and NCGG, we expect to reveal the genomic alterations of all age groups. By generating animal disease models for novel gene mutations, we hope to reveal the mechanism of disease onset and identify novel drug target, which will likely lead to novel molecularly targeted drugs. By working together among NCGM, NCVC, and NCC, we aim to develop drugs with fewer side effects. The understanding of how clonal hematopoiesis leads to cardiovascular disease and its links to lifestyle habits may help developing a preventative measure for these medical conditions.

Comments from principal researcher

Akihiko Yokoyama
National Cancer Center, Tsuruoka Metabolomics Laboratory, Team Leader

I have worked on elucidating the molecular mechanisms of leukemia in my entire research career. During the course, I discovered several protein-protein interactions critical for the disease onset and was involved in the development of drug that inhibit such molecular interactions. Very luckily, one MENIN-MLL interaction inhibitor went on to the clinical trials and is now being tested in clinical settings. Understanding of the molecular mechanism certainly leads to drug development. In this research project, JH researchers from different walks will work together to develop novel therapies for blood cancer and cardiovascular disease.

Shared Researchers

National Center for Global Health and Medicine

Department of Stem Cell Biology, Keiyo Takubo

National Cerebral and Cardiovascular Center

Research Institute, Laboratory of Cardiovascular Mosaicism, Soichi Sano

National Cancer Center

Research Institute, Division of Cancer Evolution, Kenichi Yoshida

National Center for Child Health and Development

Division of Medical Genetics, Rika Kosaki

National Center for Geriatrics and Gerontology

Department of Hematology,　Akira Katsumi