We have been studying human hematopoiesis, immunity and diseases 56In addition to this “humanized mouse” approach, we have started to ana-lyze normal and malignant human specimens by single cell RNAseq and mass cytometry. In the analysis of clinical samples, we observed inter-patient and intra-patient heterogeneity in gene expression profiles and mutational profiles of leukemic cells, motivating us to design individually-optimized treatment plans. In the past year, we have made progress in performing combined inhibi-tion of intracellular and membrane molecules in diverse sets of leukemia. Using normal blood samples, scRNAseq demonstrated that normal stem/progenitor cells appear to have key clusters of genes involved in choosing lineages in their fate decisions. Furthermore, we want to unravel how immune cell memory has been achieved in transplantation medicine. Through the combined approaches of humanized mice and single cell biology, we want to make contributions to understanding and targeting difficult-to-treat leukemia and other blood malig-nancies.since we started the lab in 2006. In hematologic malignancies, imma-ture and mature blood cells are transformed into malignancies such as leuke-mia, lymphoma or myeloma through the accumulation of multiple mutations or chromosomal aberrations. Although various anti-cancer drugs and molecu-lar targeting agents have been developed, a small number of treatment-resistant tumor cells, so-called “minimal residual disease”, has been the largest problem preventing patients from achieving sustained remission status. Therefore, we have developed NOD/SCID/Il2rgKO xenograft models to functionally define normal and malignant stem cells and to find differentially-expressed molecules as treatment targets and develop therapeutic strategies to eliminate tumor stem cells.Figure: CXCR4 expression marks CD4+ memory T-cells in patient-derived remission samples(Upper) Primary AML patient-derived T-cell samples were used for CYTOF analysis. Patients underwent marrow-ablative therapy prior to receiving a cord blood transplant (CBT). Samples from either PB or BM were subsequently collected from individuals during remis-sion following CBT. (Lower) Unsupervised clustering of CYTOF markers across T-cell subtypes demonstrated that CXCR4 expression appeared to be associated with CD4+ T memory signature genes (red dashed line).Recent Major PublicationsChuprin J, Buettner H, Seedhom MO, Greiner DL, Keck JG, Ishikawa F, Shultz LD, Brehm MA. Humanized mouse models for immuno-oncology research. Nat Rev Clin Oncol 20, 192-206 (2023)Invited presentationsKanamaru E. “Transcriptional dysregulation in acute myeloid leukemia” A*STAR – RIKEN Joint Workshop (Singapore, Singapore) November 2023Saito Y. “Understanding human leukemia using Human-ized Mice” Japan Cancer Association Annual Meeting (Yokohama, Japan) September 2023Ishikawa F. “CXCR4 induces CAR-T fate favoring memory over exhaustion leading to enduring leukemia targeting” European Hematology Association (Frankfurt, Germany)Ishikawa F. “Development of new therapeutic strategies for leukemia using NSG Humanized Mice” The Interna-tional Symposium on Advancing Humanized Mouse (Boston, USA)Ishikawa F. “Integration of PDX and genomics for thera-peutic target discovery” (Houston, USA) July 2023Laboratory for Human Disease ModelsTeam Leader: Fumihiko Ishikawa
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