Current Research and Scholarly Interests
From 2005 to 2010, my work as a clinical hematology fellow allowed me to experience first-hand how scientific advances that started in a laboratory can transform patients' lives. While many of my patients were cured of their disease with allogeneic hematopoietic stem cell transplantation, underscoring the importance of anti-tumor immunotherapy in eradicating leukemia, I witnessed face-to-face their suffering from the long-term consequence of graft-versus-host disease (GVHD). This experience was ultimately what drove me to engage in research to discover novel therapies. For this reason, I embarked on a Ph.D. program in 2010 to design antibody therapy to (i) target GVHD and (ii) target hematological malignancies. Under the mentorship of Professor Hiromitsu Nakauchi at the University of Tokyo, an international leader in hematopoiesis, I developed allele-specific anti-human leukocyte antigen (HLA) monoclonal antibodies for severe GVHD caused by HLA-mismatched hematopoietic stem cell transplantation (Nakauchi et al., Exp Hematol, 2015). This study was the first to find that anti-HLA antibodies can be used therapeutically against GVHD. That success gave me the motivation and confidence to further my research beyond targeting GVHD to targeting leukemic stem cells through my postdoctoral fellowship in the laboratory of Professor Ravindra Majeti here at Stanford University.
Many people suffer from leukemia each year, but we still don't know how to cure it completely. Recent advances in sequencing technologies have tremendously improved our understanding of the underlying mutations that drive hematologic malignancies. However, the reality is that most of the mutations are not easily "druggable," and the discovery of these mutations has not yet significantly impacted patient outcomes. This is perhaps the most crucial challenge facing a translational cancer researcher like myself. My current research is a major step toward my long-term goal of making personalized medicine a reality for patients with acute myeloid leukemia (AML) and other hematologic malignancies.
Since joining the Majeti lab, I have been targeting the ten-eleven translocation methylcytosine dioxygenase-2 (TET2) mutation, which is aberrant in leukemia at a high rate and has been studied using human-derived cells. TET2 is known to be involved in the clonal expansion of cells, and people with this mutation are more likely to suffer from hematologic malignancies. It is also known to be involved in the development of coronary artery disease, a gene that has attracted much attention in recent studies. In my field, it is an essential gene involved in the abnormal proliferation of hematopoietic stem cells. Focusing on this gene, I mapped TET2-dependent 5hmC, epigenetic and transcriptional programs matched to competitive advantage, myeloid skewing, and reduced erythroid output in TET2-deficient hematopoietic stem and progenitor cells (HSPC). Vitamin C and azacitidine restore the 5hmC landscape and phenotypes in TET2-mutant HSPCs. These findings offer a comprehensive resource for TET-dependent transcriptional regulation of human hematopoiesis and shed light on the potential mechanisms by which TET deficiency contributes to clonal hematopoiesis and malignancies. Of course, these findings would also be of value in understanding the biology of normal hematopoietic stem cells (HSCs) and various other TET2-related cancers.
And from now on, I would like to use the single-cell transplantation techniques mastered in the Majeti lab to study the behavior of normal and aberrant human HSCs using various new methods, ultimately preventing the progression of AML.
In my clinical experience, I have lost many AML patients. With the regret and sadness of losing these patients in my heart, I hope to one day contribute to developing treatments that will fundamentally change how the world treats leukemia.
