Motomi OSATO

Principal Investigator, Cancer Science Insitute of Singapore, National University of Singapore
Principal Associate, Cancer Science Institute of Singapore, National University of Singapore
Research Associate Professor, Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore
Professor, International Research Center for Medical Sciences, Kumamoto University, Japan

csimo[at]nus.edu.sg


We are investigating the mechanism behind the development of leukaemia by analyses of a key leukaemia gene, RUNX1. Through these studies, we aim to develop novel diagnostic and therapeutic methods. To achieve this, we use a range of experimental platforms, such as mouse models as well as standard biological and chemical techniques. Our best known research accomplishment is the detection of RUNX1 point mutation in acute myeloid leukaemia. This genetic change is included in the World Health Organization (WHO) leukaemia classification and being examined globally whenever a leukaemia diagnosis is made.

Research

Leukemia research towards novel treatments

We have been interrogating the mechanistic basis for leukemogenesis through the analyses of a key leukemia gene, RUNX1, aiming for the development of novel diagnostic and therapeutic methods (Figure 1). Treatment of RUNX leukemia has a dismal outcome and novel therapeutic approaches are needed. Our experimental platforms inlcude a mouse system (knockout or transgenic mice), and molecular and cellular analyses on clinical samples. Using such strategy, we have identified many diagnostic markers and treatment methods.

Identification of cis-regulatory elements associated with human diseases

Human genome consists of 1.5% of coding and 98.5% of non-coding regions. Approximately 40% of disease-related genetic changes are expected to be located within the non-coding region, particularly in cis-regulatory elements (enhancer, silencer, locus control region, and insulator) which govern expression of genes. Genetic alterations in non-coding (intronic and intergenic) regions in RUNX loci have also been suspected to be the underlying mechanism for multiple human diseases; however, cis-elements for Runx family genes remain largely unknown. Employing our own unique strategy as shown in Figure 2, we have identified multiple cis-regulatory elements. Single nucleotide polymorphisms (SNPs) within these elements would serve as predictive risk factors for human diseases, whereas pharmaceutical modulation of the elements would lead to novel therapeutic directions.

Lab Members

Selected Publications

1. Matsuo J, Kimura S, Yamamura A, Koh CP, Hossain Z, Heng DL, Kohu K, Voon DCC, Hiai H, Unno M, So JBY, Zhu F, Srivastava S, Meng T, Yeoh KG, Osato M*, Ito Y*. *co-corresponding author. Identification of stem cells in the epithelium of the stomach corpus and antrum of mice. Gastroenterology 152:218-31, 2017

2. Chin DW, Watanabe-Okochi N, Wang CQ, Tergaonkar V, Osato M. Mouse models for Core Binding Factor leukemia. Leukemia 29:1970-80, 2015

3. Koh CM, Bezzi M, Low HP, Ang WX, Teo SX, Gay FP, Al-Haddawi M, Tan SY, Osato M, Sabò A, Amati B, Wee KB, Guccione E. MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature 523:96-100, 2015

4. Wang QC, Krishnan V, Tay LS, Chooi JY, Chin DWL, Koh CP, Chooi JY, Nah GSK, Du L, Jacob B, Yamashita N, Tan TZ, Mori S, Taniuchi I, Tergaonkar V, Ito Y, Osato M. Disruption of Runx1 and Runx3 leads to bone marrow failure and leukemia predisposition due to transcriptional and DNA repair defects. Cell Reports 8:767-82, 2014

5. Koh CP, Wang QXC, Ng CEN, Ito Y, Araki M, Tergaonkar V, Huang G, Osato M. Runx1 meets MLL: epigenetic regulation of hematopoiesis by two leukemia genes. Leukemia, 27:1793-802, 2013

6. Wang QXC, Motoda L, Satake M, Ito Y, Taniuchi I, Tergaonkar V, Osato M. Runx3 deficiency results in myeloproliferative disorder in aged mice. Blood 122:562-66, 2013

7. Ng ELC, Yokomizo T, Yamashita N, Cirovic B, Jin H, Wen Z, Ito Y, Osato M. A Runx1 intronic enhancer marks hemogenic endothelial cells and hematopoietic stem cells. Stem Cells 28:1869-81, 2010

8. Osato M. Point Mutations in the RUNX1/AML1 Gene: Another Actor in RUNX Leukemia. Oncogene 23:4284–96, 2004

9. Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae S.C., Komori T, Ito Y and Littman DR. Requirement for Runx proteins in CD4 silencing at different stages of T lymphocyte development. Cell 111: 621-33, 2002

10. Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T, Suzushima H, Takatsuki K, Kanno T, Shigesada K, Ito Y. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB associated with myeloblastic leukemias. Blood 93:1817-24, 1999