Analyzing molecular basis and molecular targets for therapeutic application of adult T-cell leukemia / lymphoma by using proteomics

• Project/Area Number: 16K08665
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Osaka University
• Principal Investigator: Honma Keiichiro 大阪大学, 医学系研究科, 助教 (20505945)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 成人T細胞白血病・リンパ腫 / 成人Ｔ細胞白血病 / 悪性リンパ腫 / 血液

Outline of Final Research Achievements

We identified three proteins(ERK1/2, DUSP3, HMGB1) which up-regulated phosphorylation and expression in adult T-cell lymphoma (ATL) cell-line comparing with HTLV-I immortalized human T-cells (MT-2) by proteomics. A correlation between expression level of ATL acute type clinical samples by immunohistochemistry and proteomics data in cell-line was found only for the HMGB1. Recurrent somatic mutation of STAT3 and HMGB1 was found in 32% and 24% of ATL acute type clinical samles, respectively.We hypothesized that STAT3 mutations may induce histone modifications, such as H3K9me3 and H3K9Ac, and may expedite STAT3 binding to the HMGB1 promoter in MT2. The reduction of H3K9me and elevation of H3K9Ac histone modification in the STAT3 binding sites on the promoter of HMGB1 was observed only in the STAT3 mutant. Tumor formation was observed in nude mice injected in MT-2 expressing STAT3 mutant and HMGB1 mutant. Forthermore,administration of HMGB1 inhibitor DHMEQ prevents tumor fomation.

Academic Significance and Societal Importance of the Research Achievements

成人T細胞白血病・リンパ腫は世界的には極めて稀で、日本南西部をはじめカリブ海諸島、中央アフリカのごく一部の地域において特異的に多く見られる高悪性度の悪性リンパ腫である。とりわけ急性型は有効な治療法が確立されておらず近年になっても治療成績の改善が得られていない。全世界的な研究対象となりりにくいことから、疾患発生にレトロウイルスHTLV-Iが関与することが知られている以外、本疾患の腫瘍形成における基礎研究の知見集積に乏しい。このため治療につながる分子基盤の一部を解明した今回の研究成果は、とりわけ本疾患の好発地域である我が国において、非常に意義深いものと考えられた。

Research Products

• [Journal Article] Lymphoplasmacytic lymphoma accompanied by transformed diffuse large B-cell lymphoma with the MYD88L265P mutation (2017)
  • Author(s): Kida T1, Tanimura A, Ono A, Matsui T, Honma K, Fujita J, Maeda T, Shibayama H, Oritani K, Morii E, Kanakura Y.
  • Journal Title: Rinsho Ketsueki. Volume: 58 Pages: 155-160
  • NAID: 130005450487
  • Peer Reviewed