Research

(1) Understanding cancer based on gene expression control mechanisms at the RNA level and its therapeutic applications

It has become clear that in cancer cells, genetic information is distorted at the post-transcriptional RNA level. We have explored post-transcriptional control mechanisms of genetic information, such as RNA splicing, RNA methylation, and RNA transport, and have identified multiple therapeutic target molecules in tumor cells. Taking RNA splicing as an example, we have discovered phenomena where chromatin remodeling factors, transcription factors, and signal control factors have their functions altered or lost due to RNA splicing abnormalities, which then dominate the transcription and proliferation mechanisms of other important genes. We have elucidated these phenomena through human specimens, in vivo models, and molecular biological analyses (Inoue et al. Nature 2019, Inoue et al. Nature Genetics 2021, Nishimura et al. Cancer Sci 2022, Nishimura et al. Exp Hematol 2023).

Furthermore, we are investigating how post-transcriptional control at the RNA level is involved in subsequent expression mechanisms, including translation, approaching cancer cell vulnerabilities from the perspectives of chemical modifications and RNA transport. We are evaluating the validity of therapeutic targets, developing therapeutic applications using small molecule compounds, and applying synthetic lethality for treatment (Nishimura et al. ongoing project, Zhang and Hasegawa et al. ongoing project, Saika et al. ongoing project, etc.). We have also reported on the acquisition of stem cell clonal dominance and RAS pathway activation mechanisms due to the breakdown of splicing in "minor introns," a rare group of evolutionarily conserved introns comprising only 0.3% of all introns, numbering just over 700 (Inoue et al. Nature Genetics 2021). We are now exploring the significance of evolutionary conservation of introns from a broader perspective using mouse models (Saika et al. ongoing project). Beyond hematological cancers, we are also addressing RNA splicing abnormalities and clonal progression in lung cancer, for example, by creating in vivo models from new perspectives (Kanaoka et al. ongoing project).

(2) Functional analysis and therapeutic applications for poor prognosis leukemia and congenital diseases

With the advancement of genomic medicine, risk stratification has progressed in the field of leukemia, and personalized medicine is being introduced. However, many mutations and chromosomal abnormalities with poor prognosis still remain. Among these, we are focusing on leukemia with EVI1 overexpression caused by translocation or inversion of chromosome 3, TP53 mutant leukemia, and SETBP1 mutant leukemia. For example, in EVI1 overexpression leukemia associated with chromosomal translocation or inversion, we identified a novel variant that alters EVI1's DNA binding ability due to simultaneous splicing-related gene mutations (SF3B1 mutations) (Tanaka et al. Blood 2022). By creating in vivo models that mimic human diseases, we are now able to analyze drug resistance mechanisms and evaluate treatment effectiveness (Knorr et al. Nature Cancer 2023, Zang et al. in preparation).

For TP53 mutant leukemia and SETBP1 mutant leukemia, we are establishing new treatment strategies by integrating human and mouse data, utilizing drug discovery screening and CRISPR screening to identify cancer cell vulnerabilities. Particularly for the extremely poor prognosis TP53 mutant leukemia, the understanding of how mutated TP53 acts, whether through loss of function or functional alteration, remains inconclusive. Currently, we are focusing on the unique redox control in TP53 mutant leukemia cells to develop new treatment strategies (Nishimura et al. ongoing project). Additionally, while SETBP1 mutations are relatively common, there have been significant limitations in understanding their significance and analytical methods. Therefore, we are establishing accurate clonal progression mechanisms and novel treatment strategies using in vivo models that mimic more physiological conditions and single-cell level analysis methods (Saika et al. ongoing project). Furthermore, we are also focusing on mechanisms linking cancer and development, exploring the pathology of the congenital disorder Schinzel-Giedion syndrome, which is caused by the same SETBP1 mutations in the germline as those found in cancer, using single-cell level analysis (Yamazaki et al. in preparation).

(3) Hematopoietic control by bromodomain proteins and their application in leukemia treatment

We have reported on the abnormal regulation of the bromodomain protein BRD9 at the RNA level in cancer from a splicing perspective (IInoue et al. Nature 2019). We have detailed the stem cell differentiation control mechanism through CTCF-mediated BRD9 inhibition in normal and tumorigenic hematopoiesis at the chromatin level, and are advancing therapeutic applications in in vivo models (Xiao et al. Nat Commun 2023, Hasegawa et al. ongoing project). Furthermore, we are investigating the differences in BRD9's role between adult and fetal hematopoiesis (Zhang et al. iScience 2025), the pathogenesis of infant leukemia caused by the BRD9-NUTM1 fusion gene (Nishimura et al. in revision), and elucidating BRD9's function in regulatory T cells. Through these studies, we are expanding our understanding of the bromodomain protein BRD9's involvement in carcinogenesis and development, from pathological analysis to therapeutic applications.

BRD9 is considered an essential component of the newly identified non-canonical BAF complex, a SWI/SNF chromatin remodeling complex. However, interactions with other bromodomain proteins such as BRD4 have also been reported. We are also exploring methods to inhibit interactions between bromodomain proteins.

(4) Significance of ferroptosis as a new form of cell death in hematopoietic cells and therapeutic applications using metabolic reprogramming

Understanding metabolic reprogramming associated with cancer and aging is an essential area for pathology-based therapeutic applications. We are researching the accumulation of oxidative stress and lipid peroxidation associated with aging from the perspectives of selenoproteins and iron-dependent cell death (ferroptosis), focusing on hematopoietic stem cell differentiation bias, aging, and the onset of diseases such as MDS.

We are elucidating the relationship between age-related hematopoiesis and oxidative stress control mechanisms, as selenoprotein groups (antioxidant proteins containing selenocysteine with strong reducing properties, of which 25 types including GPX4 are known in humans) play crucial roles in maintaining hematopoietic stem cell stemness and B lymphocyte differentiation and maturation through the suppression of lipid peroxide accumulation. Model mice unable to synthesize selenoproteins exhibit blood aging phenotypes.

Interestingly, we have reported findings that provide new perspectives on age-related hematopoiesis and differentiation mechanisms. For instance, B precursor cells with accumulated lipid peroxides switch to myeloid lineage differentiation across cell lineages, while a diet rich in vitamin E improves the decrease in B lymphocytes (Aoyama and Yamazaki et al. Blood 2025).

We are also working on treatment strategies that specifically induce ferroptosis and oxidative stress in cancer cells, including AML, by inhibiting selenoproteins and their synthesis pathways. Beyond redox control mechanisms, understanding the metabolic alterations in cancer cells is a crucial issue, and we are exploring this from perspectives that link nutrition (amino acids and trace elements), stem cells, and differentiation (Yamazaki et al. ongoing project).

(5) Elucidation of interactions between hematopoietic stem cells, niche environments, and other organs

We are using novel technologies such as extracellular vesicles, single-cell chromatin analysis, and imaging to elucidate how blood cancer cells control the microenvironment that constitutes their niche, and how changes in the bone marrow microenvironment affect hematopoiesis. In particular, we are exploring organ interactions between blood cells and bones, and chromatin control abnormalities in mesenchymal stem cells that give rise to bones, using single-cell level analysis (Hayashi et al. ongoing project, Hayashi et al. Int J Hematol 2023). For example, we reported that blood cancer cells create a relatively favorable niche environment for themselves by suppressing the normal hematopoietic support ability of mesenchymal stem cells through extracellular vesicles (Hayashi et al. Cell Rep 2022). Building on this research, we are also focusing on how oxidative stress and clonal hematopoiesis in hematopoietic cells lead to unfavorable outcomes in systemic diseases.

(6) New biology that captures cells from the concept of time

Recent advances in single-cell analysis technology have revealed that cellular populations are composed of a more diverse array of cells than previously imagined, and that individual cells thought to belong to the same cell category have unique gene expression patterns and cellular phenotypes. The transformation of diversity among cell types belonging to the same category is recognized as "clonal selection," and its importance is suggested in various aspects of life, death, and disease, such as the selection of high-quality cells during development and the formation of precancerous lesions in carcinogenesis. However, current widely-used single-cell analysis methods require destructive manipulation of cells or nuclei, and the process of diversity formation can only be inferred from the transition of "snapshots" obtained from multiple different samples.

Therefore, we are challenging the implementation of new technologies to look back in time, using single-cell level base editing and barcode technologies to determine the original identity of cells with the phenotypes we are currently observing. This can be considered a pioneering research that opens up unprecedented areas using retrograde cell lineage analysis and new methods to faithfully record cell lineages and events. We are unraveling cell fates from various aspects such as carcinogenesis, differentiation commitment, fetal hematopoiesis development, and aging.