Projects

Humanized mouse

In the past decade, DNA sequencing revealed that patients with malignant diseases carry multiple somatic mutations in a patient-specific manner. The genetic complexity and heterogene-ity in cancer/leukemia patients complicates understanding of dis-ease initiation and relapse as well as drug development for human malignancies. In our acute myeloid leukemia (AML) research, we took a multiomics approach to find therapeutic targets in AML initiating cells as compared with normal hematopoietic stem and progenitor cells. By combining genetic and chemical screening, we found five critical vulnerabilities in AML: BIRC2/4, BCL2, MCL1, AURKB, and KIF10. In the presence of multiple somatic mutations and chromosomal abnormalities in patient AML cells, BIRC2/4 inhibition resulted in efficient killing of leukemic cells in vitro. Furthermore, we took advantage of patient-derived xeno-grafts to recapitulate patient leukemic status in mice followed by in vivo treatment experiments. By using two molecular targeting drugs to which individual patients showed the highest sensitivity, we confirmed profound therapeutic efficacy, as evidenced by complete elimination of patient-derived leukemic cells in the bone marrow and spleen as well as recovery of normal hematopoietic cells. Integrative analyses of somatic mutational profiling, gene expression profiling, transcription factor binding to promoter re-gions of target genes, and drug sensitivity experiments has enabled us to identify the optimal compounds for each patient. We hope to bring this precision medicine into clinical practice in the future.


Integration of genetic information into immune functions: The eQTL project

Figure: A. a whole mount bone marrow section after immunohistochemical staining with anti-human CD45 antibody. Left: no treatment control, Right: treatment with AZD5582 and ABT199.
B. Lower and higher magnification images of immunohistochemical staining with anti-hCD45 antibody and HE staining. Upper: IHC CD45, Lower: HE staining.

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