whole genome and multiomics analysis of hairy cell leukemia japansese variant

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02711
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: The University of Tokyo
• Principal Investigator: YOKOYAMA KAZUAKI 東京大学, 医科学研究所, 准教授 (00647498)
• Co-Investigator(Kenkyū-buntansha): 井元 清哉 東京大学, 医科学研究所, 教授 (10345027) ; 木村 晋也 佐賀大学, 医学部, 教授 (80359794) ; 石井 敬人 東京慈恵会医科大学, 医学部, 助教 (90814294)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 有毛細胞白血病 / 全ゲノム解析 / エンハンサー

Outline of Final Research Achievements

In an effort to elucidate the molecular pathology and develop targeted therapies for Hairy Cell Leukemia-Japanese variant (HCLjv), a rare cancer unique to Japan, we conducted whole genome analyses in comparison with Western-type HCL (positive for BRAF.pV600E mutation). Our findings revealed novel structural abnormalities in the oncogene X in 20% of HCLjv cases, suggesting tumorigenesis driven by overexpression of X through hijacking of the strong Emu enhancer. The overexpression of X frequently coexisted with loss-of-function mutations in the tumor suppressor genes Y and Z. Further investigations using cell lines demonstrated that overexpression of X activates the PI3K/Akt pathway, while loss of Y induces activation of the NFkb2 pathway. Future studies will involve in vivo analysis of the oncogenic potential of X using floxed mice engineered to specifically assess the role of X in tumorigenesis.

Free Research Field

血液腫瘍

Academic Significance and Societal Importance of the Research Achievements

我々は、現在標準治療のない、日本固有の希少がん、有毛細胞白血病日本型(HCLjv)について、その分子病態を解明と標的治療法の開発を目指して全ゲノム解析を行い、癌遺伝子X, がん抑制遺伝子Y,Zの変異を見出した。本研究により、癌遺伝子Xによる、腫瘍化のメカニズム解明と、それに基づく新しい治療法開発への道が開かれる事が期待される。