Elucidation of the genetic basis underlying lymphomagenesis by CRISPR library screening

• Project/Area Number: 18H04035
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: National Cancer Center Japan
• Principal Investigator: Kataoka Keisuke 国立研究開発法人国立がん研究センター, 研究所, 分野長 (90631383)
• Co-Investigator(Kenkyū-buntansha): 白石 友一 国立研究開発法人国立がん研究センター, 研究所, ユニット長 (70516880)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥44,330,000 (Direct Cost: ¥34,100,000、Indirect Cost: ¥10,230,000); Fiscal Year 2020: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2019: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2018: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
• Keywords: 悪性リンパ腫 / CRISPR

Outline of Final Research Achievements

Although several integrated genetic studies have identified many recurrent alterations in lymphomas, their biological relevance in lymphomagenesis remains undetermined. Here, we have performed in vivo CRISPR screening to investigate the role of these genetic alterations in a high-throughput manner. Specifically, we created CRISPR libraries targeting genes with loss-of-function mutations in lymphomas, and introduced them into hematopoietic stem/progenitor cells. The transplanted mice developed a variety of hematologic malignancies. In addition, sgRNA sequencing identified several novel drivers involved in the development of these neoplasms.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、成人T細胞白血病リンパ腫や節外性NK/T細胞リンパ腫などの難治性リンパ腫における遺伝子異常のリンパ腫発症における役割が解明された。その結果、これらの腫瘍における診断・治療戦略の改善や患者予後の向上に繋がることが期待される。さらに、本研究で用いられた生体内CRISPRスクリーニング手法による遺伝子異常の生物学的な意義の高効率な探索は、他の腫瘍や他の異常に対しても応用可能であり、更なる発展が期待される。