Updated on 2024/10/01

Information

 

写真a

 
SASAKI KENSUKE
 
Organization
Faculty of Medical Sciences Department of Clinical Medicine Assistant Professor
School of Medicine Department of Medicine(Concurrent)
Title
Assistant Professor

Degree

  • M.D., Ph.D

Research Interests・Research Keywords

  • Research theme:Development of novel treatment strategies for acute leukemia

    Keyword:Acute leukemia

    Research period: 2020.4

Papers

  • Genome-Wide CRISPR/Cas9 Screens Identify DDX19A/DDX19B As a Critical Regulator of Intrinsic Apoptosis By Regulating MCL1 mRNA Cellular Localization

    Terasaki, T; Semba, Y; Sasaki, K; Miyata, K; Yamauchi, T; Imanaga, H; Nakao, F; Hirabayashi, S; Nogami, J; Akahane, K; Inukai, T; Akashi, K; Maeda, T

    BLOOD   142   2023.11   ISSN:0006-4971 eISSN:1528-0020

  • Targeting a mitochondrial E3 ubiquitin ligase complex to overcome AML cell-intrinsic Venetoclax resistance

    Nakao F, Setoguchi K, Semba Y, Yamauchi T, Nogami J, Sasaki K, Imanaga H, Terasaki T, Miyazaki M, Hirabayashi S, Miyawaki K, Kikushige Y, Masuda T, Akashi K, Maeda T

    2023.5

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    Language:English  

  • Targeting a mitochondrial E3 ubiquitin ligase complex to overcome AML cell-intrinsic Venetoclax resistance

    Nakao, F; Setoguchi, K; Semba, Y; Yamauchi, T; Nogami, J; Sasaki, K; Imanaga, H; Terasaki, T; Miyazaki, M; Hirabayashi, S; Miyawaki, K; Kikushige, Y; Masuda, T; Akashi, K; Maeda, T

    LEUKEMIA   37 ( 5 )   1028 - 1038   2023.3   ISSN:0887-6924 eISSN:1476-5551

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    Language:English   Publisher:Leukemia  

    To identify molecules/pathways governing Venetoclax (VEN) sensitivity, we performed genome-wide CRISPR/Cas9 screens using a mouse AML line insensitive to VEN-induced mitochondrial apoptosis. Levels of sgRNAs targeting March5, Ube2j2 or Ube2k significantly decreased upon VEN treatment, suggesting synthetic lethal interaction. Depletion of either Ube2j2 or Ube2k sensitized AML cells to VEN only in the presence of March5, suggesting coordinate function of the E2s Ube2j2 and Ube2k with the E3 ligase March5. We next performed CRISPR screens using March5 knockout cells and identified Noxa as a key March5 substrate. Mechanistically, Bax released from Bcl2 upon VEN treatment was entrapped by Mcl1 and Bcl-XL and failed to induce apoptosis in March5 intact AML cells. By contrast, in March5 knockout cells, liberated Bax did not bind to Mcl1, as Noxa likely occupied Mcl1 BH3-binding grooves and efficiently induced mitochondrial apoptosis. We reveal molecular mechanisms underlying AML cell-intrinsic VEN resistance and suggest a novel means to sensitize AML cells to VEN.

    DOI: 10.1038/s41375-023-01879-z

    Web of Science

    Scopus

    PubMed

  • A Genome-Wide CRISPR-Cas9 Screen Reveals GATOR1 Complex Is a Critical Regulator of Glucocorticoid Sensitivity in B-Cell Precursor Acute Lymphoblastic Leukemia

    Imanaga, H; Semba, Y; Sasaki, K; Miyata, K; Yamauchi, T; Terasaki, T; Nakao, F; Hirabayashi, S; Nogami, J; Akashi, K; Maeda, T

    BLOOD   140   5979 - 5979   2022.11   ISSN:0006-4971 eISSN:1528-0020

  • A germinal center-associated microenvironmental signature reflects malignant phenotype and outcome of DLBCL

    Miyawaki, K; Kato, K; Sugio, T; Sasaki, K; Miyoshi, H; Semba, Y; Kikushige, Y; Mori, Y; Kunisaki, Y; Iwasaki, H; Miyamoto, T; Kuo, FC; Aster, JC; Ohshima, K; Maeda, T; Akashi, K

    BLOOD ADVANCES   6 ( 7 )   2388 - 2402   2022.4   ISSN:2473-9529 eISSN:2473-9537

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    Language:English   Publisher:Blood Advances  

    Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy, with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin (COO), genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of “unfavorable” molecular signatures.

    DOI: 10.1182/bloodadvances.2021004618

    Web of Science

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  • Genome-wide CRISPR-Cas9 screen identifies rationally designed combination therapies for <i>CRLF2</i>-rearranged Ph-like ALL

    Sasaki, K; Yamauchi, T; Semba, Y; Nogami, J; Imanaga, H; Terasaki, T; Nakao, F; Akahane, K; Inukai, T; Verhoeyen, E; Akashi, K; Maeda, T

    BLOOD   139 ( 5 )   748 - 760   2022.2   ISSN:0006-4971 eISSN:1528-0020

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    Language:English   Publisher:Blood  

    Acute lymphoblastic leukemia (ALL) harboring the IgH-CRLF2 rearrangement (IgH-CRLF2-r) exhibits poor clinical outcomes and is the most common subtype of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). While multiple chemotherapeutic regimens, including ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. To identify molecules/pathways relevant for IgH-CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of ruxolitinib using 2 IgH-CRLF2-r ALL lines that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which enabled, for the first time, highly efficient transduction of human B cells. While single-guide RNAs (sgRNAs) targeting CRLF2, IL7RA, or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B, or STAT3 did not, suggesting that STAT signaling is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and ruxolitinib sensitivity and that CRKL depletion enhances ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that blocks CRKL phosphorylation, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with ruxolitinib. We further show that combining gilteritinib with trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status. Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes.

    DOI: 10.1182/blood.2021012976

    Web of Science

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  • Targeting leukemia-specific dependence on the de novo purine synthesis pathway

    Yamauchi, T; Miyawaki, K; Semba, Y; Takahashi, M; Izumi, Y; Nogami, J; Nakao, F; Sugio, T; Sasaki, K; Pinello, L; Bauer, DE; Bamba, T; Akashi, K; Maeda, T

    LEUKEMIA   36 ( 2 )   383 - 393   2022.2   ISSN:0887-6924 eISSN:1476-5551

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    Language:English   Publisher:Leukemia  

    Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.

    DOI: 10.1038/s41375-021-01369-0

    Web of Science

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Presentations

  • B細胞リンパ腫に対するCD19 CAR-T細胞療法後のCMV再活性化

    森 康雄, 西原 博英, 山口 晃平, 平川 聖也, 中垣 秀隆, 佐々木 謙介, 迫田 哲平, 陳之内 文昭, 宮脇 恒太, 山内 拓司, 島 隆宏, 菊繁 吉謙, 平安山 友子, 國崎 祐哉, 加藤 光次, 赤司 浩一

    日本血液学会学術集会  2023.10  (一社)日本血液学会

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    Language:English  

Professional Memberships

  • 日本造血・免疫細胞療法学会

  • 日本血液学会

  • 日本内科学会

Research Projects

  • 急性リンパ性白血病の新規診断法開発

    2025 - 2026

    日本学術振興会  科学研究費助成事業  若手研究

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    Grant type:Scientific research funding