Elucidation of the mechanism of ATLL development and identification of leukemic stem cell profiles using a mouse model

• Project/Area Number: 20K08715
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Kameda Takuro 宮崎大学, 医学部, 助教 (30468029)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ATLL / HBZ / CARD11 / 癌 / シグナル伝達 / ウイルス / 成人T細胞白血病・リンパ腫 / 腫瘍幹細胞

Outline of Research at the Start

成人T細胞白血病・リンパ腫（ATLL）では、CARD11変異に代表されるT細胞抗原受容体-NF-κB経路の遺伝子異常がリンパ球腫瘍化に直接的に関与すると推測されている。またこれらの遺伝子異常は腫瘍幹細胞様の性質を有する希少な細胞分画に集積し、階層的な腫瘍クローンを形成すると推測されている。本研究では、CARD11変異などのATLLでみられる遺伝子異常を導入した複数のマウスを用いて、腫瘍化機序の解明と標的治療の開発を行う。また、CARD11変異マウス、ヒト検体、ヒト検体の異種移植マウスなど、複数のモデルで腫瘍幹細胞様分画の遺伝子発現解析を行い、腫瘍幹細胞様の性質がどのように維持されるのかを明らかにする。

Outline of Final Research Achievements

We analyzed mice transfected with the viral gene HBZ (HBZ TG), mice transfected with a CARD11 mutation that activates the TCR-NFκB pathway (CARD11mut TG), and mice with a combination of these abnormalities (compound TG). HBZ TG and CARD11mut TG cause a slow onset of lymphoproliferative disease, and compound TG causes a rapid onset of lymphoproliferative disease with T cell infiltration of organs, and that these mouse models recapitulate ATL pathology.
Compound TG showed increased expression of a variety of proliferation-related gene sets and recapitulated approximately 80% of the aberrant gene sets found in human acute type ATL specimens, suggesting that NFκB activation associated with mutations in TCR-NFκB pathway molecules and expression of the viral gene HBZ form the molecular basis of ATL.

Academic Significance and Societal Importance of the Research Achievements

HBZ TG、CARD11変異TG、二重異常TGの各マウスの解析から、ATLの分子病態を明らかにした（Communications Biology. Kameda et al. 2022）。二重異常TGマウスでは、ATL検体と類似したTCR/NF-κB経路の活性化と、生後半年でのリンパ増殖性疾患の発症が観察され、また、CD4 T cellにおいてはヒトATL検体と類似した遺伝子発現異常が観察されたことから、ATLの基本的な分子病態の形成機序が明らかになった。今後、分子病態に即した新規治療の開発が期待される。

Research Products

• [Journal Article] Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma (2023)
  • Author(s): Kameda T, Kataoka K, Kitanaka A, Ogawa S, Shimoda K（他31名、36番目）
  • Journal Title: Haematologica Volume: - Issue: 8 Pages: 2178-2191
  • DOI: 10.3324/haematol.2022.281510
  • Peer Reviewed / Open Access
• [Journal Article] Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma (2022)
  • Author(s): Kameda T, Shide K, Tahira Y, Sekine M, Sato S, Ishizaki J, Takeuchi M, Akizuki K, Kamiunten A, Shimoda H, Toyama T, Maeda K, Yamashita K, Kawano N, Kawano H, Hidaka T, Yamaguchi H, Kubuki Y, Kitanaka A, Matsuoka H, Shimoda K
  • Journal Title: Viruses Volume: 14 Issue: 4 Pages: 710-710
  • DOI: 10.3390/v14040710
  • Peer Reviewed / Open Access
• [Journal Article] Oncogenic isoform switch of tumor suppressor BCL11B in adult T-cell leukemia/lymphoma. (2022)
  • Author(s): Permatasari HK, Nakahata S, Ichikawa T, Fauzi YR, Kiyonari H, Shide K, Kameda T, Shimoda K, Ono M, Taki T, Taniwaki M, Futakuchi, Morishita K.
  • Journal Title: Experimental Hematology Volume: 111 Pages: 41-49
  • DOI: 10.1016/j.exphem.2022.04.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oral histone deacetylase inhibitor tucidinostat ( <scp>HBI</scp> ‐8000) in patients with relapsed or refractory adult T‐cell leukemia/lymphoma: Phase <scp>IIb</scp> results (2022)
  • Author(s): Utsunomiya A, Izutsu K, Jo T, Yoshida S, Tsukasaki K, Ando K, Choi I, Imaizumi Y, Kato K, Kurosawa M, Kusumoto S, Miyagi T, Ohtsuka E, Sasaki O, Shibayama H, Shimoda K, Takamatsu Y, Takano K, Yonekura K, Makita S, Taguchi J, Gillings M, Onogi H, Tobinai K.
  • Journal Title: Cancer Science Volume: 113 Issue: 8 Pages: 2778-2787
  • DOI: 10.1111/cas.15431
  • Peer Reviewed / Open Access
• [Journal Article] CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma (2022)
  • Author(s): Takuro Kameda, ...Sho Kubota.... , Kazuya Shimoda
  • Journal Title: Communications Biology Volume: 5 Issue: 1 Pages: 1309-1309
  • DOI: 10.1038/s42003-022-04284-x
  • Peer Reviewed / Open Access
• [Journal Article] Whole-genome landscape of adult T-cell leukemia/lymphoma (2022)
  • Author(s): Kogure Y, Kameda T, Koya J, Yoshimitsu M, Nosaka K, Yasunaga JI, Imaizumi Y, Watanabe M, Saito Y, Okada A, Kakiuchi N, Nannya Y,Kitanaka A, Hidaka M, Nakano N, Utsunomiya A, Sica RA, Acuna-Villaorduna A, Janakiram M, Shah U, Shibata T, Takeuchi K, Ogawa S, Ye BH, Shimoda K, Kataoka K（他20名、26番目）
  • Journal Title: Blood Volume: 139 Issue: 7 Pages: 967-982
  • DOI: 10.1182/blood.2021013568
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1 (2021)
  • Author(s): Koya J, Saito Y, Kameda T, Kogure Y, Yuasa M, Nagasaki J, McClure MB, Shingaki S, Tabata M, Tahira Y, Akizuki K, Kamiunten A, Sekine M, Shide K, Kubuki Y, Hidaka T, Kitanaka A, Nakano N, Utsunomiya A, Togashi Y, Ogawa S, Shimoda K, Kataoka K
  • Journal Title: Blood Cancer Discovery Volume: 2 Issue: 5 Pages: 450-467
  • DOI: 10.1158/2643-3230.bcd-21-0044
  • NAID: 120007145001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Higher average chemotherapy dose intensity improves prognosis in patients with aggressive adult T‐cell leukemia/lymphoma (2020)
  • Author(s): Sekine M, Kameda T, Shide K, Maeda K, Toyama T, Kawano N, Takeuchi M, Kawano H, Sato S, Ishizaki J, Kukita T, Kamiunten A, Akizuki K, Tahira Y, Shimoda H, Hidaka T, Yamashita K, Matsuoka H, Kitanaka A, Kubuki Y, Shimoda K
  • Journal Title: European Journal of Haematology Volume: 106 Issue: 3 Pages: 398-407
  • DOI: 10.1111/ejh.13565
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of soluble CADM1 as a novel marker for adult T-cell leukemia/lymphoma. (2020)
  • Author(s): Nakahata S, Syahrul C, Nakatake A, Sakamoto K, Yoshihama M, Nishikata I, Ukai Y, Matsuura T, Kameda T, Shide K, Kubuki Y, Hidaka T, Kitanaka A, Ito A, Takemoto S, Nakano N, Saito M, Iwanaga M, Sagara Y, Mochida K, Amano M, Maeda K, Sueoka E, Okayama A, Utsunomiya A, Shimoda K, Watanabe T, Morishita K.
  • Journal Title: Haematologica Volume: 105 Issue: 2 Pages: 1-1
  • DOI: 10.3324/haematol.2019.234096
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma (2022)
  • Author(s): Kameda T,Kataoka K,Kamiunten A,Hidaka M,Miyoshi H,Nakano N,Nosaka K,Yoshimitsu M,Yasunaga J,Kogure Y,Shide K,Miyahara M,Sakamoto T,Hidaka T,Kubuki Y,Koya J,Imaizumi Y,Kato K,Tokunaga M,Takaori A,Miyazaki Y,Akashi K,Ishitsuka K,Matsuoka M,Ohshima K,Watanabe T,Kitanaka A,Utsunomiya A,Ogawa S,Shimoda K
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Loss of EZH2 does not affect the severity of murine myeloproliferative neoplasms with CALR mutation (2021)
  • Author(s): Ayako Kamiunten, Yuki Tahira，Keiichi Akizuki，Masaaki Sekine， Takuro Kameda，Kotaro Shide，Tomonori Hidaka，Yoko Kubuki， Kazuya Shimoda
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] CARD11E626K and HBZ form ATL-like gene expression profile and acceralate T-cell proliferation (2021)
  • Author(s): Takuro Kameda, Yasunori Kogure，Takako Yokomizo， Ayako Kamiunten，Junji Koya，Kotaro Shide，Sho Kubota， Yuki Tahira，Keiichi Akizuki，Masaaki Sekine，Tomonori Hidaka， Yoko Kubuki，Daisuke Morishita，Akira Kitanaka，Goro Sashida， Keisuke Kataoka，Seishi Ogawa，Kazuya Shimoda
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] MALT1 阻害薬の開発とATL に対する治療効果の検討 (2020)
  • Author(s): 上運天綾子、森下大輔、亀田拓郎、木暮泰寛、幣光太郎、田平優貴、南谷泰仁、依田成玄、秋月渓一、関根雅明、日高智徳、久冨木庸子、水谷明生、杉山緑、有川泰由、三宅洋、片岡圭亮、小川誠司、下田和哉
  • Organizer: 第82 回日本血液学会学術集会
• [Presentation] ATL で好発する機能獲得型変異CARD11E626KはマウスにおけるHBZ 誘導性の炎症を亢進させる (2020)
  • Author(s): 亀田拓郎、幣光太郎、上運天綾子、田平優貴、秋月渓一、関根雅明、日高智徳、久冨木庸子、杉山緑、森下大輔、下田和哉
  • Organizer: 第82 回日本血液学会学術集会
• [Presentation] 化学療法のdose intensity とmogamulizumab 投与がaggressive ATLL の予後を改善する (2020)
  • Author(s): 関根雅明、亀田拓郎、幣光太郎、前田宏一、外山孝典、河野徳明、武内正紀、河野浩、佐藤誠一、石崎淳三、久木田稔正、上運天綾子、秋月渓一、田平優貴、下田晴子、日高智徳、山下清、松岡均、下田和哉
  • Organizer: 第82 回日本血液学会学術集会
• [Presentation] マルチオミクス単一細胞解析によるHTLV-1 感染状態およびATL における細胞動態の網羅的解明 (2020)
  • Author(s): 古屋淳史、斎藤優樹、亀田拓郎、木暮泰寛、Marni Mcclure、新垣清登、吉藤康太、田畑真梨子、上運天綾子、幣光太郎、下田和哉、片岡圭亮
  • Organizer: 第82 回日本血液学会学術集会
• [Presentation] Whole-Genome Analysis of Adult T-Cell Leukemia/Lymphoma (2020)
  • Author(s): Kogure Y,Kameda T, Koya J, Kamiunten A, Shide K, Hidaka T, Kubuki Y, Yoshimitsu M, Nosaka K, Imaizumi Y :
  • Organizer: 62nd ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Dissecting Multicellular Ecosystems of HTLV-1 Infection and ATL By Multi-Omics Single Cell Analysis (2020)
  • Author(s): Koya J,Saito Y, Kameda T, Kogure Y, Marni B McClure, Shingaki S, Tabata M, Kamiunten A, Shide K, Shimoda K :
  • Organizer: 62nd ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] CARD11 Mutation Induces Oligoclonal Expansion of T-Cells, and Accelerates ATL Development in Combination with HBZ (2020)
  • Author(s): Kameda T,Shide K, Kamiunten A, Yuki T, Sekine M, Akizuki K, Hidaka T, Kubuki Y, Sugiyama M, Morishita D :
  • Organizer: 62nd ASH Annual Meeting and Exposition
  • Int'l Joint Research