Kyushu University Academic Staff Educational and Research Activities Database
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Takahiro Maeda Last modified date:2022.06.30

Professor / Division of Precision Medicine
Research Center for Precision Medicine
Faculty of Medical Sciences


Graduate School


Homepage
https://kyushu-u.pure.elsevier.com/en/persons/takahiro-maeda
 Reseacher Profiling Tool Kyushu University Pure
https://precision.kyushu-u.ac.jp/en/
Academic Degree
MD., Ph.D.
Country of degree conferring institution (Overseas)
No
Field of Specialization
Hematology/Oncology
ORCID(Open Researcher and Contributor ID)
orcid.org/0000-0003-4530-6460
Total Priod of education and research career in the foreign country
15years01months
Research
Research Interests
  • Goals of our research projects are to:
    1. Identify novel targets for acute leukemia therapy.
    2. Determine molecular mechanisms underlying fetal global repression in adult erythroid cells.
    3. Determine the role of the transcription factor LRF/ZBTB7A in hematopoietic cellular differentiation.
    keyword : Acute leukemia, Sickle cell disease, Differentiation of hematopoietic lineage cells
    2016.10.
Current and Past Project
  • Hemoglobinopathies, such as sickle cell disease (SCD) and thalassemia, are among the greatest public health concerns in the world. Although new therapeutic modalities, such as gene therapy, are currently being tested, there is a pressing need for pharmacologic approaches to treat general patient populations. Our long-term goal is to develop a compound(s) that induces fetal-type globin (HbF) production by targeting the transcriptional complex regulating globin switching. The objective of this application is to determine molecular mechanisms underlying the LRF-NuRD-mediated γ-globin silencing and identify a mean(s) to target them. Our central hypothesis is that the LRF-containing NuRD complex is a potential target for HbF reactivation therapy. The rationale for the proposed research is that understanding the LRF/NuRD-mediated globin regulation will provide greater understanding of the transcriptional complex regulating γ-globin repression and facilitate development of novel therapeutic strategies for HbF induction therapy.
  • Goal of this study is to identify novel targets for leukemia therapy using a genome-wide CRISPR/Cas9 screen.
Academic Activities
Papers
1. Jake C Swartzel, Michael J Bond, Andreas P Pintado-Urbanc, Mehana Daftary, Mackenzie W Krone, Todd Douglas, Evan J Carder, Joshua T Zimmer, Takahiro Maeda, Matthew D Simon, Craig M Crews, Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC, ACS Chem Biol, 10.1021/acschembio.2c00145, 2022.06, The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 serves as a chemical biology tool to interrogate DcpS degradation and associated changes in RNA processes in different cellular contexts, which may be an attractive strategy for the treatment of AML and other DcpS-dependent genetic disorders..
Presentations
1. Sasaki K, Yamauchi T, Semba Y, Nogami J, Imanaga H, Terasaki T, Nakao F, Akahane K, Inukai T, Verhoeyen E, Akashi K and Maeda T, Genome-Wide CRISPR-Cas9 Screen Identifies Rationally Designed Combination Therapies Relevant for CRLF2-Rearranged Ph-like ALL, American Society of Hematology annual meeting, Atlanta, USA, 2021.12, Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL, also known as BCR-ABL1-like ALL) is a disease entity of B-cell ALL that exhibits a gene expression profile, similar to that of Philadelphia chromosome-positive ALL. Ph-like ALL is categorized into two disease subtypes: “ABL-class”- and “CRLF2/JAK pathway”-types, both of which harbor gene alterations that constitutively activate cytokine/growth factor-related signals. Ph-like ALL with the CRLF2 rearrangement exhibits poor clinical outcomes and is the most common subtype of Ph-like ALL. Tyrosine kinase inhibitor (TKI)-based treatment regimens are effective in treating ABL-class type Ph-like ALL; however, no standard regimen has been established for the CRLF2/JAK pathway type. While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. Thus, novel approaches are needed to treat CRLF2/JAK pathway type Ph-like ALL, in particular for CRLF2-rearranged (CRLF2-r) ALL..
2. Yamauchi T, Miyawaki K, Semba Y, Nakao F, Nogami J, Sugio T, Sasaki K, Canver MC, Osborne S, Pinello L, Taylor D, Bauer DR, Akashi K, Maeda T., PAICS, a de novo purine synthetic enzyme, is a novel target for AML therapy., American Society of Hematology annual meeting, Orland, USA, 2019.09.
3. SembaY, Yamauchi T, Nakao F, Nogami J, Canver MC, Pinello L, Bauer DE, Akashi K, Maeda T., CRISPR-Cas9 screen identifies XPO7 as a potential therapeutic target for TP53-mutated AML., American Society of Hematology annual meeting, Orland, USA, 2019.09.
Membership in Academic Society
  • American Society of Hematology
  • Japanese Society of Hematology
  • Society of Hematologic Oncology
  • Japan Society for Hematopoietic Cell Transplantation
  • Japanese Cancer Association
  • Japanese Society of Internal Medicine
  • Japan Society of Transfusion Medicine and Cell Therapy