Molecular Pathogenesis of Follicular Lymphoma and its early/precursor lesions

• Project/Area Number: 19K16554
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: University of Yamanashi
• Principal Investigator: OISHI Naoki 山梨大学, 大学院総合研究部, 准教授 (90623661)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 濾胞性リンパ腫 / ISFN / BCL2 / B細胞リンパ腫 / in situ リンパ腫 / 遺伝子異常 / 遺伝子発現異常

Outline of Research at the Start

濾胞性リンパ腫(FL)は今なお治癒が困難なB細胞リンパ腫で、近年患者数が増加している。FLは染色体転座t(14;18)(q32;q21)/IgH-BCL2によるアポトーシス抵抗性にエピゲノム異常や免疫逃避といったさまざまな付加的形質が加わって発症する。しかし、それぞれの付加的な異常が発生・進展のどの段階で獲得され、どの形質がFLの形成を決定づけるのかは明らかでない。本研究では、FLの前駆・早期病変で良性の経過を示すin situ follicular neoplasm: ISFNの分子異常を統合的に解析し、t(14;18)を有したB細胞がFLに至るメカニズムを明らかにする。

Outline of Final Research Achievements

1) Lymph nodes (LNs) dissected for non-hematolymphoid malignancies were screened by immunohistochemistry (IHC) for BCL2. The incidence of in situ follicular neoplasm (ISFN) in Japan was 2.1%. 2) ISFN exhibited CD20+, CD10+, BCL6+, and BCL2+ by IHC, similar to follicular lymphoma (FL). All the patients with identified ISFNs developed no overt FL after median follow-up of 58 months. 3) In addition to BCL2 gene rearrangement, ISFN harbored some FL-associated gene mutations, including KMT2D and CREBBP. No EZH2 mutation was found.

Academic Significance and Societal Importance of the Research Achievements

濾胞性リンパ腫は本邦においても頻度の高いリンパ腫である。本研究では、濾胞性リンパ腫の前駆病変と考えられるin situ follicular neoplasm (ISFN)の特徴を解析した。本邦におけるISFNは、非リンパ腫患者の2.1%に認められ、濾胞性リンパ腫に類似した免疫形質を有することが明らかになった。一方、ISFNが単独で発見された場合、濾胞性リンパ腫に進展するリスクは低いと考えられた。濾胞性リンパ腫で認められる遺伝子異常の一部は、ISFNの段階から生じていることが示唆された。以上は、ISFNから濾胞性リンパ腫への進展を考察する上で、重要なデータである。

Research Products

• [Journal Article] Early Transformation to Classic Hodgkin Lymphoma in a Chemotherapy-naïve Chronic Lymphocytic Leukemia Patient upon Initial Treatment with Ibrutinib (2021)
  • Author(s): Koshiishi Megumi、Odate Toru、Nakagawa Yukie、Suzuki Jun、Kumagai Takuya、Kawashima Ichiro、Yamamoto Takeo、Nakajima Kei、Tanaka Masaru、Oishi Naoki、Kondo Tetuso、Kirito Keita
  • Journal Title: Internal Medicine Volume: 60 Issue: 20 Pages: 3305-3308
  • DOI: 10.2169/internalmedicine.6979-20
  • NAID: 130008104384
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-10-15
  • Peer Reviewed
• [Journal Article] Heme activates platelets and exacerbates rhabdomyolysis-induced acute kidney injury via CLEC-2 and GPVI/FcRγ (2021)
  • Author(s): S. Oishi, N. Tsukiji, S. Otake, N. Oishi, T. Sasaki, T. Shirai, Y. Yoshikawa, K. Takano, H. Shinmori, T. Inukai, T. Kondo, K. Suzuki-Inoue
  • Journal Title: blood advances Volume: 5 Issue: 7 Pages: 2017-2026
  • DOI: 10.1182/bloodadvances.2020001698
  • Peer Reviewed / Open Access
• [Journal Article] Expression of CD1 molecules and colony‐stimulating factor 1 receptor in indeterminate cell histiocytosis (2021)
  • Author(s): Kinoshita Manao、Ogawa Youichi、Honobe Akiko、Tomita Ozumi、Oishi Naoki、Shimada Shinji、Kondo Tetsuo、Kawamura Tatsuyoshi
  • Journal Title: The Journal of Dermatology Volume: - Issue: 7 Pages: 1086-1089
  • DOI: 10.1111/1346-8138.15857
  • Peer Reviewed
• [Journal Article] Progression of Papillary Thyroid Carcinoma to Anaplastic Carcinoma in Metastatic Lymph Nodes: Solid/Insular Growth and Hobnail Cell Change in Lymph Nodes Are Predictors of Subsequent Anaplastic Transformation (2021)
  • Author(s): Odate Toru、Oishi Naoki、Kawai Masataka、Tahara Ippei、Mochizuki Kunio、Akaishi Junko、Ito Koichi、Katoh Ryohei、Kondo Tetsuo
  • Journal Title: Endocrine Pathology Volume: - Issue: 3 Pages: 347-356
  • DOI: 10.1007/s12022-021-09674-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High‐grade uterine sarcoma with osteosarcomatous differentiation arising from a MED12‐ mutated leiomyoma, a case report (2021)
  • Author(s): Le Minh‐Khang、Omori Makiko、Oishi Naoki、Oi Megumi、Fukasawa Hiroko、Hirata Shuji、Kondo Tetsuo
  • Journal Title: Pathology International Volume: 71 Issue: 3 Pages: 199-203
  • DOI: 10.1111/pin.13065
  • Peer Reviewed
• [Journal Article] Nodal EBV-positive polymorphic B cell lymphoproliferative disorder with plasma cell differentiation: clinicopathological analysis of five cases (2021)
  • Author(s): Satou Akira、Tabata Tetsuya、Suzuki Yuka、Sato Yasuharu、Tahara Ippei、Mochizuki Kunio、Oishi Naoki、Takahara Taishi、Yoshino Tadashi、Tsuzuki Toyonori、Nakamura Shigeo
  • Journal Title: Virchows Archiv Volume: 478 (5) Issue: 5 Pages: 969-976
  • DOI: 10.1007/s00428-020-02967-6
  • Peer Reviewed
• [Journal Article] Genetic differences in follicular thyroid carcinoma between Asian and Western countries: a systematic review (2020)
  • Author(s): Odate Toru、Oishi Naoki、Vuong Huy Gia、Mochizuki Kunio、Kondo Tetsuo
  • Journal Title: Gland Surgery Volume: 9 Issue: 5 Pages: 1813-1826
  • DOI: 10.21037/gs-20-356
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of MGMT methylation status using high-performance liquid chromatography in newly diagnosed glioblastoma (2020)
  • Author(s): Hanihara M, Miyake K, Watanabe A, Yamada Y, Oishi N, Kawataki T, Inukai T, Kondo T, Kinouchi H.
  • Journal Title: Clin Epigenetics Volume: 12(1) Issue: 1 Pages: 174-174
  • DOI: 10.1186/s13148-020-00968-5
  • Peer Reviewed / Open Access
• [Journal Article] Loss of 5-Hydroxymethylcytosine is an Epigenetic Hallmark of Thyroid Carcinomas with TERT Promoter Mutations (2020)
  • Author(s): Oishi Naoki、Vuong Huy Gia、Mochizuki Kunio、Kondo Tetsuo
  • Journal Title: Endocrine Pathology Volume: 31 Issue: 4 Pages: 359-366
  • DOI: 10.1007/s12022-020-09652-z
  • Peer Reviewed
• [Journal Article] Identification of Recurrent TERT Promoter Mutations in Intrathyroid Thymic Carcinomas (2020)
  • Author(s): Tahara Ippei、Oishi Naoki、Mochizuki Kunio、Oyama Toshio、Miyata Kazuyuki、Miyauchi Akira、Hirokawa Mitsuyoshi、Katoh Ryohei、Kondo Tetsuo
  • Journal Title: Endocrine Pathology Volume: 31 Issue: 3 Pages: 274-282
  • DOI: 10.1007/s12022-020-09635-0
  • Peer Reviewed
• [Journal Article] Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma (2020)
  • Author(s): Oishi Naoki、Hundal Tanya、Phillips Jessica L.、et al.
  • Journal Title: Haematologica Volume: - Issue: 6 Pages: 1714-1724
  • DOI: 10.3324/haematol.2019.245860
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Composite monoclonal B‐cell lymphocytosis and MYD88 L265P‐positive lymphoplasmacytic lymphoma in a patient with IgM light chain amyloidosis: Case report (2020)
  • Author(s): Oishi Naoki、Inoue Tomohiro、Odate Toru、Mochizuki Kunio、Ohashi Kenichi、Kirito Keita、Kondo Tetsuo
  • Journal Title: Pathology International Volume: - Issue: 7 Pages: 458-462
  • DOI: 10.1111/pin.12937
  • Peer Reviewed
• [Journal Article] Targetability of STAT3-JAK2 fusions: implications for T-cell lymphoproliferative disorders of the gastrointestinal tract (2019)
  • Author(s): Hu Guangzhen、Phillips Jessica L.、Dasari Surendra、Jacobs Hailey K.、Luchtel Rebecca A.、Oishi Naoki、Hundal Tanya、Ahmed Nada H.、Satou Akira、Epstein Alan L.、Bennani N. Nora、Nowakowski Grzegorz S.、Murray Joseph A.、Feldman Andrew L.
  • Journal Title: Leukemia Volume: 34 Issue: 5 Pages: 1467-1471
  • DOI: 10.1038/s41375-019-0678-3
• [Journal Article] Assessment of peritoneal elastic laminal invasion improves survival stratification of pT3 and pT4a colorectal cancer: a meta-analysis (2019)
  • Author(s): Odate Toru、Vuong Huy Gia、Mochizuki Kunio、Oishi Naoki、Kondo Tetsuo
  • Journal Title: Journal of Clinical Pathology Volume: 72 Issue: 11 Pages: 736-740
  • DOI: 10.1136/jclinpath-2019-206056
• [Journal Article] Constitutional abnormality of nuclear membrane proteins in small cell lung carcinoma (2019)
  • Author(s): Wang Jieying、Kondo Tetsuo、Nakazawa Tadao、Oishi Naoki、Mochizuki Kunio、Katoh Ryohei
  • Journal Title: Virchows Archiv Volume: 475 Issue: 4 Pages: 407-414
  • DOI: 10.1007/s00428-019-02597-7
• [Journal Article] Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma (2019)
  • Author(s): Luchtel Rebecca A.、Zimmermann Michael T.、Hu Guangzhen、ら
  • Journal Title: Blood Volume: 133 Issue: 26 Pages: 2776-2789
  • DOI: 10.1182/blood.2019000626
• [Journal Article] Cutaneous lesions of angioimmunoblastic T‐cell lymphoma: Clinical, pathological, and immunophenotypic features (2019)
  • Author(s): Oishi Naoki、Sartori‐Valinotti Julio C.、Bennani N. Nora、Wada David A.、He Rong、Cappel Mark A.、Feldman Andrew L.
  • Journal Title: Journal of Cutaneous Pathology Volume: 46 Issue: 9 Pages: 637-644
  • DOI: 10.1111/cup.13475