Analysis of ATL progression by CD30 signaling and its biomarkers

• Project/Area Number: 19K16580
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Nakashima Makoto 東京大学, 大学院新領域創成科学研究科, 特任研究員 (30733232)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: CD30 / CD30シグナル / ATL / 染色体不安定性 / HTLV-1 / CD30 signaling / Chromosome instability / 成人T細胞白血病

Outline of Research at the Start

申請者らは最新の研究で、CD30陽性HTLV-1感染細胞はCD30リガンドを介したCD30シグナルにより感染者の病態の進行と共に増加し、細胞内で染色体異常を誘発させ、病態の進行に直接関与しうることを報告した。
本申請研究はこれらを発展させたものであり、CD30陽性HTLV-1感染細胞内の染色体構造異常および遺伝子異常は前癌状態の時点で他の集団に先駆けて生じていること、さらにCD30リガンドを介したCD30刺激が染色体構造異常および遺伝子異常を促進させることを明らかにする。
本研究の成果は、抗CD30抗体医薬による前癌状態への早期治療介入および発症後の治療介入を支持するエビデンスになると期待される。

Outline of Final Research Achievements

We previously reported that a biological link between the expression of CD30, which serves as a marker for ATL progression, and the actively proliferating fraction of HTLV-1-infected cells. To further pursue this finding, we examined whether genomic aberrations are caused by CD30 signaling.
In this study, we found that CD30 signaling induced DNA double-strand breaks (DSBs) via an increase of intracellular reactive oxygen species (ROS) and an accumulation of chromosomal aberrations. Furthermore, CGH analysis revealed that CD30+ATL cells accumulated chromosomal aberrations, focal gains and losses, compared with CD30-ATL cells in ATL individuals.
Taken together these results, accumulation of chromosomal aberrations in patient derived CD30+ATL cells indicates high chromosomal instability, suggesting that CD30 signaling triggers it.

Academic Significance and Societal Importance of the Research Achievements

本研究結果から、CD30シグナルがATLの病態進展にゲノムレベルで寄与し得ることを示した。したがってCD30は急性型、リンパ腫型などのアグレッシブタイプだけでなく、くすぶり型、慢性型を含む早期癌の段階においても治療標的になり得ることが示唆された。抗CD30抗体医薬であるブレンツキシマブ・ベドチンの有効な投与法開発に資する研究成果であると考えられる。

Research Products

• [Journal Article] Differentiation of Hodgkin lymphoma cells by reactive oxygen species and regulation by heme oxygenase‐1 through HIF‐1α (2021)
  • Author(s): Nakashima Makoto、Watanabe Mariko、Nakano Kazumi、Uchimaru Kaoru、Horie Ryouichi
  • Journal Title: Cancer Science Volume: 112 Issue: 6 Pages: 2542-2555
  • DOI: 10.1111/cas.14890
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a novel diagnostic test algorithm for human T-cell leukemia virus type 1 infection with line immunoassay replacement of western blotting: a collaborative study for performance evaluation of diagnostic assays in Japan, (2020)
  • Author(s): Okuma K, Kuramitsu M, Niwa T, et al.(40人中17番目)
  • Journal Title: Retrovirology Volume: 17 Issue: 1 Pages: 26-26
  • DOI: 10.1186/s12977-020-00534-0
  • Peer Reviewed / Open Access
• [Journal Article] A high-throughput detection method for the clonality of Human T-cell leukemia virus type-1-infected cells in vivo (2020)
  • Author(s): Saito M, Hasegawa H, Yamauchi S, Nakagawa S, Sasaki D, Nao N, Tanio M, Wada Y, Matsudaira T, Momose H, Kuramitsu M, Yamagishi M, Nakashima M, Nakahata S, Iha H, Ogata M, Imaizumi Y, Uchimaru K, Morishita K, Watanabe T, Miyazaki Y, Yanagihara K.
  • Journal Title: Int J Hematol. Volume: 112 Issue: 3 Pages: 300-306
  • DOI: 10.1007/s12185-020-02935-5
  • Peer Reviewed / Open Access
• [Journal Article] Activation of PERK-ATF4-CHOP pathway as a novel therapeutic approach for efficient elimination of HTLV-1-infected cells (2020)
  • Author(s): Ikebe E, Matsuoka S, Tezuka K, Kuramitsu M, Okuma K, Nakashima M,, Seiichiro Kobayashi S, Makiyama J, Yamagishi M, Oyadomari S, Uchimaru K, Hamaguchi I
  • Journal Title: Blood adv Volume: 4 Issue: 9 Pages: 1845-1858
  • DOI: 10.1182/bloodadvances.2019001139
  • Peer Reviewed / Open Access
• [Journal Article] Successful clinical sequencing by molecular tumor board in an elderly patient with refractory Sezary syndrome (2020)
  • Author(s): Hijikata K, Yokoyama K (co-1st and co-corresponding author), Yokoyama N, Matsubara Y, Shimizu E, Nakashima M, Yamagishi M, Ota Y, Lim L, Yamaguchi R, Ito M, Tanaka Y, Denda T, Tani K, Yotsuyanagi H, Imoto S, Miyano S, Uchimaru K, Tojo A.
  • Journal Title: JCO Precis Oncol Volume: 4 Issue: 4 Pages: 534-560
  • DOI: 10.1200/po.19.00254
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Differentiation of Hodgkin lymphoma cells by reactive oxygen species and its regulation by heme oxigenase-1 through HIF-1α (2020)
  • Author(s): Makoto Nakashima, Mariko Watanabe, Kazumi Nakano, Kaoru Uchimaru, Ryouichi Horie
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] CD30シグナルによるATL病態進展機序の解析 (2020)
  • Author(s): 中島誠
  • Organizer: コホート・生体試料支援プラットフォーム（CoBiA） 令和2年度若手支援研究成果発表会
• [Presentation] CD30シグナルによるATL病態進展機序の解析 (2020)
  • Author(s): 中島 誠
  • Organizer: 新学術領域研究「学術研究支援基盤形成」コホート・生体試料支援プラットフォーム 令和元年度 若手支援研究成果発表会
• [Presentation] Differentiation of HL cells by ROS and its regulation by heme oxygenase-1 through HIF-1α (2020)
  • Author(s): 中島 誠
  • Organizer: 第82回 日本血液学会学術集会