The Association of STAT3 Activation with Interferon Therapy in Adult T-Cell Leukemia Lymphoma

• Project/Area Number: 19K17862
• 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: University of the Ryukyus
• Principal Investigator: MORICHIKA KAZUHO 琉球大学, 医学(系)研究科(研究院), 助教 (90793943)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2021: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: adult T cell lymphoma / STAT3 / immunohistochemistry / DNA sequencing / DLBCL / リン酸化 / DNAシークエンシング / びまん性大細胞型B細胞リンパ腫 / GCB型 / non-GCB型 / シークエンス / 免疫染色 / 成人T細胞性白血病 / 免疫組織化学染色 / 遺伝子変異 / JAK-STAT3経路 / 予後予測マーカー / HTLV-1 / JAK-STAT経路 / 内科 / 成人T細胞性白血病リンパ腫 / インターフェロン療法

Outline of Research at the Start

本研究では九州・沖縄地方において発症頻度が高い成人T細胞性白血病(Adult T-cell　leukemia/lymphoma, ATLL)におけるSTAT3タンパクとIFN-αの腫瘍増殖抑制効果との関連性の詳細な解明を目指す。この研究によって、IFN-α/zudovudine療法の治療標的が同定され、治療適応基準と予後改善への貢献を目指す。

Outline of Final Research Achievements

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. We attempted to clarify the clinicopathological significance of JAK-STAT pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3, 5, 6 (pSTAT) were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression-free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL.

Academic Significance and Societal Importance of the Research Achievements

上記に示す様にくすぶり型ATLにおける新たな予後因子を提唱した。さらに我々はびまん性大細胞型B細胞リンパ腫におけるpSTAT3の意義についても解析した。pSTAT3陽性GCB型は５年生存率が92%であるのに対し、pSTAT3陽性non-GCB型は45%と、Cell of OriginによりpSTAT3発現の臨床的意義が異なっていた。pSTAT3陽性GCB型は多変量解析でも予後良好因子として抽出された。遺伝子変異解析の結果、MYD88変異、EZH2変異、EBウイルス感染、BCL2/MYCの再構成といった予後不良とされる分子異常を伴う頻度が有意に低いことが予後良好と関連する背景として考えられた。

Research Products

• [Journal Article] Clinically amyopathic dermatomyositis manifested after the allogeneic haematopoietic stem cell transplantation: Case presentation and literature review (2023)
  • Author(s): Miyagi R, Nakachi S, Tamaki Y, Doi M, Nakajima T, Kitamura S, Tomori S, Hanashiro T, Tamaki K, Morichika K, Nishi Y, Morishima S, Fukushima T, Masuzaki H.
  • Journal Title: Mod Rheumatol Case Rep Volume: 7 Pages: 102-107
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma (2021)
  • Author(s): K. Morichika, K. Karube, S. Sakihama, R. Watanabe, M. Kawaki, Y. Nishi, S. Nakachi, S. Okamoto, T. Takahara, A. Satou, S. Shimada, K. Shimada, T. Tsuzuki, T. Fukushima, S. Morishima and H. Masuzaki
  • Journal Title: Am J Surg Pathol Volume: - Issue: 6 Pages: 832-840
  • DOI: 10.1097/pas.0000000000001691
  • Peer Reviewed / Open Access
• [Journal Article] Genetic profile of adult T‐cell leukemia/lymphoma in Okinawa: Association with prognosis, ethnicity, and HTLV‐1 strains (2021)
  • Author(s): Sakihama Shugo、Morichika Kazuho、Saito Rumiko、Miyara Megumi、Miyagi Takashi、Hayashi Masaki、Uchihara Junnosuke、Tomoyose Takeaki、Ohshiro Kazuiku、Nakayama Shingo、Nakachi Sawako、Morishima Satoko、Sakai Kazuko、Nishio Kazuto、Masuzaki Hiroaki、Fukushima Takuya、Karube Kennosuke
  • Journal Title: Cancer Science Volume: 112 Issue: 3 Pages: 1300-1309
  • DOI: 10.1111/cas.14806
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathological features of adult T-cell leukemia/lymphoma with HTLV-1-infected Hodgkin and Reed-Sternberg-like cells (2021)
  • Author(s): Kennosuke Karube, Mitsuyoshi Takatori, Shugo Sakihama, Yuma Tsuruta, Takashi Miyagi, Kazuho Morichika, Sakiko Kitamura, Norihiro Nakada, Masaki Hayashi, Shohei Tomori, Iwao Nakazato, Kazuiku Ohshiro, Naoki Imaizumi, Yara Yukie Kikuti, Naoya Nakamura, Satoko Morishima, Hiroaki Masuzaki, Takuya Fukushima
  • Journal Title: Blood Advances Volume: 5 Pages: 198-206
  • Peer Reviewed / Open Access
• [Journal Article] Full-length HLA sequencing in adult T cell leukemia-lymphoma uncovers multiple gene alterations. (2021)
  • Author(s): Tamaki K, Morishima S, Suzuki S, Shigenari A, Nomura I, Yokota Y, Morichika K, Nishi Y, Nakachi S, Okamoto S, Fukushima T, Shiina T, Masuzaki H.
  • Journal Title: Leukemia Volume: 35 Issue: 10 Pages: 2998-3001
  • DOI: 10.1038/s41375-021-01403-1
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T-cell leukemia/lymphoma. (2019)
  • Author(s): Morichika K, Karube K, Kayo H, Uchino S, Nishi Y, Nakachi S, Okamoto S, Morishima S, Ohshiro K, Nakazato I, Fukushima T, Masuzaki H.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 9 Pages: 2982-2991
  • DOI: 10.1111/cas.14114
  • NAID: 120006937802
  • Peer Reviewed / Open Access
• [Presentation] 眼房水のIL-10/IL-6濃度比が診断と病勢評価に有用であった原発性網膜硝子体リンパ腫 (2022)
  • Author(s): 森近一穂
  • Organizer: 第336回 日本内科学会九州地方会
• [Presentation] Indolent ATLにおける診断時血清sIL-2R値の2倍化は優れた急性転化予測指標である (2021)
  • Author(s): 森近一穂、森島聡子、北村紗希子、友利昌平、玉城啓太、西由希子、仲地佐和子、宮城敬、大城一郁、福島卓也、加留部謙之輔、益崎裕章
  • Organizer: 第7回HTLV-1学会
• [Presentation] 遺伝子全領域の解析により明らかになったATLに生じる多彩なHLA遺伝子異常 (2021)
  • Author(s): 森島聡子、玉城啓太、鈴木進悟、重成敦子、野村育美、横田雄太郎、森近一穂、西由希子、仲地佐和子、岡本士毅、福島卓也、椎名隆、益崎裕章
  • Organizer: 第7回HTLV-1学会
• [Presentation] 血清sIL-2R濃度の持続的上昇はインドレント型ATL における急性転化の予測に有用である (2020)
  • Author(s): 森近一穂
  • Organizer: 日本内科学会九州地方会
• [Presentation] 血清sIL-2R濃度の持続的上昇はインドレント型ATL における急性転化の予測に有用である (2020)
  • Author(s): 森近一穂
  • Organizer: 日本血液学会九州地方会