microRNAとスーパーエンハンサーに着目した悪性リンパ腫のPVT1の役割解明

• Project/Area Number: 21K16248
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Wakayama Medical University
• Principal Investigator: 細井 裕樹 和歌山県立医科大学, 医学部, 講師 (00646036)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Granted (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: PVT1 / lncRNA / 8q24染色体転座 / スーパーエンハンサー / microRNA

Outline of Research at the Start

悪性リンパ腫患者数は高齢化により増加傾向で、有害事象の少ない分子標的薬の開発につながる悪性リンパ腫の発症機序解明は重要である。8q24染色体転座を有する悪性リンパ腫の予後は不良であり、新たな治療法の開発が望まれている。本研究では8q24に存在する非コードRNAであるPVT1に着目して研究を行う。PVT1は1980年代に同定されたがその機能解析は未だ不十分である。これまでの申請者の研究活動から①PVT1内のmicroRNAと②転座により形成されるスーパーエンハンサーによるPVT1への影響に着目して悪性リンパ腫発症におけるPVT1の役割を明らかにする。

Outline of Annual Research Achievements

悪性リンパ腫の中でも特に8番染色体長腕24バンド（8q24）染色体転座を有する悪性リンパ腫の予後は不良であり、治療に難渋することがある。そのため、8q24染色体転座を有する悪性リンパ腫の腫瘍化の機構を明らかにして、新たな治療薬開発につなげることは重要である。染色体転座点近傍には腫瘍発症に重要な遺伝子が存在する。8q24転座点近傍にはガン遺伝子MYCとその下流にPlasmacytoma variant translocation 1 (PVT1)が存在する。PVT1はlong intergenic non-coding RNA（lncRNA）である。本研究の目的は、①PVT1内のmicroRNA (miR)と②転座により形成されるスーパーエンハンサーによるPVT1への影響に着目して悪性リンパ腫発症におけるPVT1の役割を明らかにすることである。
令和4年度はPVT1 5’発現抑制効果を十分に得るためにPVT1 5’領域を欠失させるCRISPRベクターを設計してPVT1 5’発現抑制下での腫瘍細胞増殖変化の検討を試みた。CRISPRベクターをレンチウイルスを用いて8q24転座を有する悪性リンパ腫細胞株への導入を試みている。また、PVT1の腫瘍化に関わる要因としてPVT1プロモーター領域の変異に関しても検討している。悪性リンパ腫症例の骨髄液またはリンパ節から抽出したDNAを用いてプロモーター配列の変異を検討している。

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

COVID診療等により実験に制約が生じた。またCRISPR実験にさらなる工夫が必要のため時間を要している。

Strategy for Future Research Activity

PVT1 5'発現抑制効果を十分得られるようなCRISPRの実験系を確立する。また、PVT1をアンチセンスオリゴヌクレオチドを用いて発現抑制できないかを血液腫瘍以外の細胞株を用いて検討し、PVT1発現抑制方法を最適化する。

Research Products

• [Journal Article] Rituximab Monotherapy for Grade 2-3 Lymphomatoid Granulomatosis with Central Nervous System Involvement in a Patient Receiving Methotrexate for Rheumatoid Arthritis (2023)
  • Author(s): Hosoi Hiroki、Tanaka Ken、Sakaki Ayaka、Kosako Hideki、Iwamoto Ryuta、Matsumoto Ai、Arakawa Fumiko、Yamoto Toshikazu、Murata Shogo、Mushino Toshiki、Murata Shin-Ichi、Nakao Naoyuki、Ohshima Koichi、Sonoki Takashi
  • Journal Title: Internal Medicine Volume: 62 Issue: 13 Pages: 1977-1982
  • DOI: 10.2169/internalmedicine.0636-22
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2023-07-01
  • Peer Reviewed
• [Journal Article] An evaluation based on relative treatment intensity in older patients treated with reduced-dose R-THP-COP therapy for diffuse large B-cell lymphoma: A multicenter retrospective cohort study (2023)
  • Author(s): Hiroi Takayuki、Hosoi Hiroki、Kuriyama Kodai、Murata Shogo、Morimoto Masaya、Mushino Toshiki、Nishikawa Akinori、Tamura Shinobu、Sonoki Takashi
  • Journal Title: Journal of Geriatric Oncology Volume: 14 Issue: 1 Pages: 101396-101396
  • DOI: 10.1016/j.jgo.2022.10.011
  • Peer Reviewed / Open Access
• [Journal Article] Highly efficient Runx1 enhancer eR1-mediated genetic engineering for fetal, child and adult hematopoietic stem cells (2023)
  • Author(s): Koh CP., Bahirvani AG., Wang CQ., Yokomizo T., Ng CEL., Du L., Tergaonkar V., Voon DC., Kitamura H., Hosoi H., Sonoki T., Michelle MMH., Tan LJ., Niibori-Nambu A., Zhang Y., Perkins AS., Hossain Z., Tenen DG., Ito Y., Venkatesh B., Osato M.
  • Journal Title: Gene Volume: 851 Pages: 147049-147049
  • DOI: 10.1016/j.gene.2022.147049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Severe systemic inflammation mimicking TAFRO syndrome following COVID-19 (2023)
  • Author(s): Tane Misato、Kosako Hideki、Hosoi Hiroki、Tabata Kayoko、Hiroi Takayuki、Osawa Kosuke、Iwamoto Ryuta、Murata Shogo、Mushino Toshiki、Murata Shin-Ichi、Araki Shin-Ichi、Fujii Takao、Sonoki Takashi
  • Journal Title: International Journal of Hematology Volume: - Issue: 3 Pages: 374-380
  • DOI: 10.1007/s12185-023-03589-9
  • Peer Reviewed
• [Journal Article] Successful combination treatment with rituximab, steroid pulse therapy, plasma exchange and romiplostim for very severe TAFRO syndrome (2022)
  • Author(s): Sakaki Ayaka、Hosoi Hiroki、Kosako Hideki、Furuya Yoshiaki、Iwamoto Ryuta、Hiroi Takayuki、Murata Shogo、Mushino Toshiki、Murata Shin-Ichi、Sonoki Takashi
  • Journal Title: Leukemia and Lymphoma Volume: 63 Issue: 10 Pages: 2499-2502
  • DOI: 10.1080/10428194.2022.2074992
  • Peer Reviewed
• [Journal Article] Use of thromboelastography before the administration of hemostatic agents to safely taper recombinant activated factor VII in acquired hemophilia A: a report of three cases (2022)
  • Author(s): Hosoi Hiroki、Akagi Yuina、Mushino Toshiki、Takeyama Masahiro、Minoura Naoto、Hiroi Takayuki、Furuya Yoshiaki、Morimoto Masaya、Murata Shogo、Tamura Shinobu、Sonoki Takashi
  • Journal Title: Thrombosis Journal Volume: 20 Issue: 1 Pages: 28-28
  • DOI: 10.1186/s12959-022-00387-x
  • Peer Reviewed / Open Access
• [Journal Article] Sudden Cardiac Death in a Patient with Thrombotic Thrombocytopenic Purpura: A Case Report (2022)
  • Author(s): Yoshida Kikuaki、Murata Shogo、Morimoto Masaya、Mushino Toshiki、Tanaka Ken、Yamashita Yusuke、Hosoi Hiroki、Nishikawa Akinori、Tamura Shinobu、Hatakeyama Kinta、Matsumoto Masanori、Sonoki Takashi
  • Journal Title: Hematology Reports Volume: 14 Issue: 2 Pages: 203-209
  • DOI: 10.3390/hematolrep14020027
  • Peer Reviewed / Open Access
• [Journal Article] Acute-type acquired hemophilia A after COVID-19 mRNA vaccine administration: A new disease entity? (2022)
  • Author(s): Hosoi Hiroki、Tane Misato、Kosako Hideki、Ibe Masaki、Takeyama Masahiro、Murata Shogo、Mushino Toshiki、Sonoki Takashi
  • Journal Title: Journal of Autoimmunity Volume: 133 Pages: 102915-102915
  • DOI: 10.1016/j.jaut.2022.102915
  • Peer Reviewed
• [Journal Article] Liquid biopsy of plasma and cerebrospinal fluid are useful for detection of intravascular lymphoma with central nervous system symptoms alone. (2022)
  • Author(s): Hosoi H, Tanigawa I, Kosako H, Okamoto A, Iwamoto R, Koh J, Mori M, Hiroi T, Mushino T, Murata S, Murata SI, Tomita A, Sonoki T.
  • Journal Title: Annals of Hematology Volume: 101 Issue: 3 Pages: 709-711
  • DOI: 10.1007/s00277-021-04572-2
  • Peer Reviewed
• [Journal Article] Prolonged Epstein-Barr virus reactivation coincidence with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. (2022)
  • Author(s): Hosoi H, Matsuyama Y, Murata S, Mushino T, Sonoki T.
  • Journal Title: Leukemia Lymphoma Volume: 63 Issue: 4 Pages: 1009-1012
  • DOI: 10.1080/10428194.2021.2005047
  • Peer Reviewed
• [Journal Article] Severe aplastic anemia after COVID-19 mRNA vaccination: Causality or coincidence? (2022)
  • Author(s): Tabata Shotaro、Hosoi Hiroki、Murata Shogo、Takeda Satomi、Mushino Toshiki、Sonoki Takashi
  • Journal Title: Journal of Autoimmunity Volume: 126 Pages: 102782-102782
  • DOI: 10.1016/j.jaut.2021.102782
  • Peer Reviewed
• [Journal Article] Tirabrutinib maintenance therapy for a patient with high-dose methotrexate-ineligible primary central nervous system lymphoma. (2022)
  • Author(s): Okamura T, Hosoi H, Matsufusa T, Akagi Y, Iwamoto R, Kosako H, Murata S, Mushino T, Murata SI, Sonoki T.
  • Journal Title: Annals of Hematology Volume: 101 Issue: 6 Pages: 1379-1381
  • DOI: 10.1007/s00277-021-04744-0
  • Peer Reviewed
• [Journal Article] Composite Epstein-Barr Virus-associated T-lymphoblastic and Peripheral T-cell Lymphomas: A Clonal Study (2021)
  • Author(s): Hosoi Hiroki、Mushino Toshiki、Nakashima Kazutaka、Kuriyama Kodai、Tamura Shinobu、Murata Shogo、Imadome Ken-Ichi、Ohshima Koichi、Sonoki Takashi
  • Journal Title: Internal Medicine Volume: 60 Issue: 13 Pages: 2119-2123
  • DOI: 10.2169/internalmedicine.6572-20
  • NAID: 130008060437
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-07-01
  • Peer Reviewed / Open Access
• [Journal Article] A cluster of BK polyomavirus‐associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation (2021)
  • Author(s): Hosoi Hiroki、Murata Shogo、Suzuki Tetsuro、Li Tian‐Cheng、Hatanaka Kazuo、Tanaka‐Taya Keiko、Mushino Toshiki、Kuriyama Kodai、Tamura Shinobu、Hanaoka Nobuyoshi、Sonoki Takashi
  • Journal Title: Transplant Infectious Disease Volume: 23 Issue: 6
  • DOI: 10.1111/tid.13736
  • Peer Reviewed / Open Access
• [Journal Article] Role of bone marrow aspiration clots for evaluating cellularity: comparison of clots, biopsies, and smears (2021)
  • Author(s): Tanaka Ken、Hosoi Hiroki、Kodama Rieko、Tabata Shotaro、Hiroi Takayuki、Kida Yohei、Mushino Toshiki、Murata Shogo、Tamura Shinobu、Ikeda Takeshi、Sonoki Takashi
  • Journal Title: Annals of Hematology Volume: 100 Issue: 11 Pages: 2843-2844
  • DOI: 10.1007/s00277-021-04596-8
  • Peer Reviewed
• [Journal Article] Dose-adjusted high-dose chemotherapy with autologous stem cell transplantation for elderly (70 years old) lymphoma patients (2021)
  • Author(s): Hosoi Hiroki、Murata Shogo、Mushino Toshiki、Tamura Shinobu、Sonoki Takashi
  • Journal Title: Annals of Hematology Volume: - Issue: 1 Pages: 205-207
  • DOI: 10.1007/s00277-020-04373-z
  • Peer Reviewed
• [Journal Article] Detection of pulse rate elevation by Apple Watch in a patient with bronchiolitis obliterans syndrome after allogeneic stem cell transplantation (2021)
  • Author(s): Mushino Toshiki、Nishikawa Akinori、Hiroi Takayuki、Matsuyama Yoriko、Hosoi Hiroki、Murata Shogo、Tamura Shinobu、Sonoki Takashi
  • Journal Title: Annals of Hematology Volume: 101 Issue: 4 Pages: 897-899
  • DOI: 10.1007/s00277-021-04625-6
  • Peer Reviewed
• [Journal Article] Intracranial Hemorrhage in a Patient with TAFRO Syndrome Treated with Cyclosporine A and Rituximab (2021)
  • Author(s): Akagi Yuina、Kato Takashi、Yamashita Yusuke、Hosoi Hiroki、Murata Shogo、Yamamoto Shuto、Warigaya Kenji、Nakao Taisei、Murata Shinichi、Sonoki Takashi、Tamura Shinobu
  • Journal Title: Medicina Volume: 57 Issue: 9 Pages: 971-971
  • DOI: 10.3390/medicina57090971
  • Peer Reviewed / Open Access
• [Journal Article] Management of warm autoimmune hemolytic anemia related to band 3-positive colon carcinoma (2021)
  • Author(s): Matsuyama Yoriko、Hosoi Hiroki、Horitani Ryosuke、Kawamoto Shinichiro、Hashimoto Tadayuki、Kimura Masatomo、Nakai Hiroaki、Mushino Toshiki、Sonoki Takashi
  • Journal Title: Annals of Hematology Volume: - Issue: 6 Pages: 1343-1344
  • DOI: 10.1007/s00277-021-04714-6
  • Peer Reviewed
• [Journal Article] 当院におけるテレビ会議システムを用いた遠隔同種移植後長期フォローアップ外来の取り組み. (2021)
  • Author(s): 蒸野寿紀、西川彰則、堀善和、小浴秀樹、栩野祐一、吉田菊晃、森本将矢、高木良、上田かやこ、細井裕樹、村田祥吾、田村志宣、園木孝志
  • Journal Title: 日本造血細胞移植学会誌 Volume: 10 Pages: 113-117
  • NAID: 130008025168
  • Peer Reviewed
• [Presentation] 慢性GVHD増悪後のEBV/CMV 再活性化に伴い発症した移植後ギランバレー症候群の一例 (2023)
  • Author(s): 細井裕樹、太根美聡、小浴秀樹、榊絢朱、和田嘉允、中山宜昭、弘井孝幸、堀善和、山下友佑、蒸野寿紀、村田祥吾、園木孝志
  • Organizer: 第45回日本造血・免疫細胞療法学会総会
• [Presentation] 当院で原疾患再発に対して2度目の同種移植を行った症例での初回と2回目の移植経過の比較検討 (2023)
  • Author(s): 太根美聡、細井裕樹、小浴秀樹、堀善和、山下友佑、蒸野寿紀、村田祥吾、西川彰則、園木孝志
  • Organizer: 第45回日本造血・免疫細胞療法学会総会
• [Presentation] Non-coding Cλ mRNA controlled by super-enhancer affectes MYC and BCL6 expression in B-cell lymphoma (2022)
  • Author(s): Hiroki Hosoi, Tadashi Okamura, Kentaro Suzuki, Daiki Kajioka, Motomi Osato, Gen Yamada, Takashi Sonoki
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Comparison of PCNSL patients treated in neurosurgery and hematology departments (2022)
  • Author(s): Tadashi Okamura, Hiroki Hosoi, Junya Fukai, Takayuki Hiroi, Yusuke Ymashita, Toshiki Mushin, Shogo Murata, Naoyuki Nakao, Takashi Sonoki
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Combination therapy with rituximab, plasma exchange, and romiplostim for severe TAFRO syndrome (2022)
  • Author(s): Ayaka Sakaki, Hiroki Hosoi, Hideki Kosako, Yoshiaki Furuya, Takayuki Hiroi, Shogo Murata, Toshiki Mushino, Takashi Sonoki
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] 当科における活性型血液凝固第VII因子製剤を投与された後天性血友病A症例の検討 (2021)
  • Author(s): 細井裕樹、蒸野寿紀、弘井孝幸、村田祥吾、西川彰則、田村志宣、園木孝志
  • Organizer: 第43回日本血栓止血学会学術集会
• [Presentation] Reduction of IgG level after R-chemo might be a predictive factor for prognosis in B-cell lymphoma. (2021)
  • Author(s): Tabata S, Hosoi H, Tanaka K, Hiroi T, Kida Y, Mushino T, Murata S, Tamura S, Ikeda T, Sonoki T.
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Long-term follow-up of DLBCL patients aged over 80 years treated with reduced dose R-THP-COP. (2021)
  • Author(s): Hiroi T, Hosoi H, Kuriyama K, Morimoto M, Murata S, Mushino T, Tamura S, Sonoki T.
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Role of BM aspiration clots: comparison of clots, biopsies, and smears for evaluating BM cellularity. (2021)
  • Author(s): Tanaka K, Hosoi H, Kodama R, Tabata S, Hiroi T, Kida Y, Mushino T, Murata S, Tamura S, Ikeda T, Sonoki T.
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Primary myelofibrosis showing Sweet's syndrome, progressive dysplasia, and mutational evolution. (2021)
  • Author(s): Kosako H, Hosoi H, Tanaka M, Iwamoto R, Iwahashi Y, Mori Y, Tanigawa I, Sakaki A, Takeda S, Yokoya Y, Tabata S, Yoshida K, Tochino Y, Hiroi T, Yamashita Y, Mushino T, Murata S, Nishikawa A, Tamura S, Jinnin M, Sonoki T.
  • Organizer: 第83回日本血液学会学術集会