Fauzi YR, Nakahata S, Shimoda K, Matsuura T, Hagiwara S, Inoue K, Moritake H, Morishita K . Anti-transferrin receptor antibody (JST-TFR09/PPMX-T003) induces ferroptosis in adult T-cell leukemi2025 · 記述言語： 英語 掲載種別： 研究論文（学術雑誌） 出版者・発行元： Biochemical and Biophysical Research Communications Previously, we developed a complete human IgG TFR1 antibody (JST-TFR09/PPMX-T003) that showed a potentially practical therapeutic effect against adult T-cell leukemia/lymphoma (ATLL) in vitro and in vivo. In the present study, to elucidate the molecular mechanism underlying ATLL cell death induced by anti-TFR1 antibodies, we performed comprehensive gene expression analysis and mass spectrometry on ATLL cells treated with PPMX-T003 antibody. These results suggest that PPMX-T003 antibody treatment of ATLL cell lines induces ferroptosis mediated by ferritin degradation. PPMX-T003 antibody-treated ATLL cell lines showed a decrease in ferritin proteins, an increase in ferrous iron (Fe<sup>2+</sup>), reactive oxygen species (ROS) generation, and malondialdehyde as induction of lipid peroxidation. Moreover, treatment with a ferroptosis inhibitor (ferroportin-1) inhibited the cell death induced by PPMX-T003 antibody in ATLL cells. Furthermore, NCO4A and LC3-II were induced following antibody treatment, and ferritin degradation was inhibited by lysosomal inhibitors, suggesting that ferritin degradation depends on autolysosomal system activation. Here, we introduce ferroptosis as one of the potential mechanisms of PPMX-T003 antibody, which is promising for future therapeutic antibodies targeting a wide range of leukemia and cancers, including ATLL. DOI： 10.1016/j.bbrc.2025.151564 Scopus PubMed
Chiba N, Suzuki S, Enriquez-Vera D, Utsunomiya A, Kubuki Y, Hidaka T, Shimoda K, Nakahata S, Yamada T, Morishita K . Succinic semialdehyde derived from the gut microbiota can promote the proli2024 · 記述言語： 英語 掲載種別： 研究論文（学術雑誌） 出版者・発行元： Heliyon Adult T-cell leukemia/lymphoma (ATLL) is a refractory blood cancer with severe immunodeficiency resulting from retroviral infection. ATLL develops in only 5 % of HTLV-1-infected individuals, but the entire mechanism of ATLL progression remains unknown. Since recent studies have reported that the gut microbiome influences the progression of various diseases, we hypothesized that ATLL is also related to the gut microbiome and aimed to investigate this relationship. We analyzed the taxonomic and functional profiles of the gut microbiota of ATLL patients (n = 28) and HTLV-1-infected individuals (n = 37). We found that the succinic semialdehyde (SSA) synthesis pathway was significantly enriched in the gut microbiome of ATLL patients (P = 0.000682), and Klebsiella, whose abundance was significantly greater in ATLL patients and high-risk HTLV-1-infected individuals (P = 0.0326), was the main contributor to this pathway. Administration of SSAs to ATLL cell lines resulted in significant cell proliferation. Herein, we propose that the gut microbiome can regulate ATLL progression via metabolites. DOI： 10.1016/j.heliyon.2024.e38507 Scopus PubMed
Mochida K, Nakahata S, Suzuki Y, Inoue K, Moriguchi S, Yamashita A, Amano M, Morishita K . Prognostic analysis of smoldering ATLL with skin eruptions based on genomic aberrations. . Jo2023 · 記述言語： 英語 掲載種別： 研究論文（学術雑誌） 出版者・発行元： Journal of Dermatological Science Background: Patients with smoldering ATLL often present with a skin eruption due to skin infiltration of ATLL cells. Although skin eruption type is known to be associated with prognosis based on its pattern, it is unknown why different types of skin eruptions are associated with different prognoses. Objective: Genomic analysis of patients with skin eruptions of smoldering ATLL will be performed to determine the mechanism of ATLL development and its association with prognosis. Methods: DNA from skin biopsy specimens was used for targeted sequencing of 280 genes to examine the association between genomic variation and prognosis. Results: Due to the small number of smoldering ATLL patients (27 cases), we could not find a clear relationship between skin eruption and prognosis in this study. Genomic analysis identified 247 genomic variants (108 genes), with an average of 9.2 variants and 3.2 variants as driver genes. Pathway analysis of the driver genes showed activation of the pathway associated with HTLV-1 infection, as well as activation of the signaling pathway observed throughout ATLL. Furthermore, multivariate analysis identified age>70 years and STAT3 mutation as prognostic risk factors and TBL1XR1 mutation as a risk factor for progression-free survival. Conclusion: Although the small number of patient samples did not allow us to determine a prognostic association with skin eruption, STAT3 mutation was identified as a prognostic risk factor for smoldering ATLL with skin eruption. Further studies are needed to increase the number of patients with this disease. DOI： 10.1016/j.jdermsci.2023.02.001 Scopus PubMed CiNii Research
