Elucidation of the high-grade pathogenesis of universal mature B cell tumor model by using comprehensive gene editing
| Project/Area Number |
21K16274
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
Mizutani Shinsuke 京都府立医科大学, 医学(系)研究科(研究院), 助教 (40883088)
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| Project Period (FY) |
2021-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | B細胞性リンパ腫 / 多発性骨髄腫 / PDPK1 / RSK2 |
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| Outline of Research at the Start |
B細胞性リンパ腫（B cell lymphoma; BCL）、多発性骨髄腫（Multiple myeloma; MM）は、高頻度造血器腫瘍であるが、難治症例の克服が、いまだ重要課題として残されている。本研究ではヒト正常B細胞由来不死化細胞株にPDPK1-RSK2シグナル恒常的活性化を誘導した「BCL疾患横断的・普遍的モデル細胞」を作成し、高度造腫瘍性、細胞死刺激抵抗性獲得、染色体・遺伝子不安定性、抗腫瘍細胞免疫回避機構を誘導する分子異常の同定を目指す。さらに患者細胞の解析によって、その臨床的意義について明らかにし、高度難治BCL、MMの克服戦略開発のための基盤知見を確立する
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| Outline of Final Research Achievements |
B cell lymphoma (BCL) and multiple myeloma (MM) are highly prevalent hematopoietic tumors, and overcoming refractory cases remains an important challenge. In this study, we generated "BCL disease-cross-sectional and universal model cells" by inducing PDPK1-RSK2 signaling homeostatic activation in an immortalized human normal B cell-derived cell line, and performed a comprehensive screening of human whole genome CRISPR/Cas9 gene knockout against these cells to identify cells with high tumorigenicity, resistance to cell death stimulation, chromosomal and genetic instability We are in the process of identifying molecular abnormalities that induce high tumorigenicity, resistance to cell death stimulation, chromosomal and genetic instability, and anti-tumor cell immune evasion mechanisms.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究でBCL、MMにおけるPDPK1-RSK2シグナルの恒常的活性化の病型横断的・普遍的な病態形成する「がん抑制遺伝子、がん遺伝子」が同定できれば、染色体・遺伝子不安定性獲得によるクローン性進化、骨髄由来抑制系細胞誘導機序等の解明に繋がり、一部の症例に認める高度治療抵抗性獲得病態を司る付加的分子異常の解明と克服に大きな一歩となるだけでなく、他のがん種に関する応用研究も期待できる。
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Report
(3 results)
Research Products
(9 results)
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[Journal Article] Watchful waiting is an acceptable treatment option for asymptomatic primary ocular adnexal mucosa‐associated lymphoid tissue lymphoma: A retrospective study2022
Author(s)
Mizuhara Kentaro, Kobayashi Tsutomu, Nakao Mitsushige, Takahashi Ryoichi, Kaneko Hiroto, Shimura Kazuho, Hirakawa Koichi, Uoshima Nobuhiko, Wada Katsuya, Kawata Eri, Isa Reiko, Fujino Takahiro, Tsukamoto Taku, Mizutani Shinsuke, Shimura Yuji, Yoneda Akiko, Watanabe Akihide, Sotozono Chie, Kuroda Junya
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Journal Title
Cancer Medicine
Volume: 12
Issue: 3
Pages: 3134-3144
DOI
Related Report
Peer Reviewed
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[Journal Article] The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma.2022
Author(s)
Isa R, Horinaka M, Tsukamoto T, Mizuhara K, Fujibayashi Y, Taminishi-Katsuragawa Y, Okamoto H, Yasuda S, Kawaji-Kanayama Y, Matsumura-Kimoto Y, Mizutani S, Shimura Y, Taniwaki M, Sakai T, Kuroda J.
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Journal Title
Int J Mol Sci.
Volume: 23
Issue: 6
Pages: 2919-2936
DOI
Related Report
Peer Reviewed / Open Access
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