Understanding the mechanism of cell tumorigenesis promoted by essential thrombocythemia specific transcriptional network

• Project/Area Number: 20H03715
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Juntendo University
• Principal Investigator: Komatsu Norio 順天堂大学, 医学部, 特任教授 (50186798)
• Co-Investigator(Kenkyū-buntansha): 森下 総司 順天堂大学, 医学部, 特任助教 (10635866) ; 今井 美沙 順天堂大学, 大学院医学研究科, 非常勤助教 (50709003) ; 荒木 真理人 順天堂大学, 大学院医学研究科, 客員教授 (80613843)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2020: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 骨髄増殖性腫瘍 / 小胞体ストレス応答因子 / 本態性血小板血症 / 血小板 / 巨核球 / 小胞体ストレス / 転写因子 / 診断マーカー

Outline of Research at the Start

フィラデルフィア染色体陰性の骨髄増殖性腫瘍は、造血幹・前駆細胞に体細胞変異が生じ、血球の異常増加や骨髄の線維化を呈する造血器腫瘍である。申請者は最近、骨髄増殖性腫瘍に含まれる疾患群のひとつである本態性血小板血症の患者血小板に含まれるRNAの網羅的な解析から、当該疾患に特異的な転写ネットワークの活性化が生じている証拠を掴んだ。そこで本研究では、このネットワークの活性化が生じる分子基盤を解明するとともに、本態性血小板血症の発症への関与を明らかにすることを目的とする。

Outline of Final Research Achievements

Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of hematopoietic malignancies in which somatic mutations occur in hematopoietic stem/progenitor cells, resulting in an abnormal increase in blood cells and fibrosis of the bone marrow. In this study, we analyzed the clinical significance of the CREB3L1 gene, which specifically expresses on platelets derived from patients with MPNs, and its impact on the development of MPNs.
Analysis of platelet-derived RNA from patients with MPNs suggested that the CREB3L1 gene may be a clinically valuable gene that can be used not only for the diagnosis but also for prognosis prediction of MPNs. Furthermore, a series of analyses using CD34-positive cells isolated from the peripheral blood of patients with MPNs demonstrated that the CREB3L1 gene is required for tumor cell differentiation and survival in MPNs.

Academic Significance and Societal Importance of the Research Achievements

本研究では，血液学的に前例のないCREB3L1遺伝子の高発現が，MPNs発症にどう関与するかを明らかにしたことが，学術的に意義のある点である。
さらに，CREB3L1の発現がMPNsの診断や予後予測に有用である可能性を示し，CREB3L1の発現を抑制すると腫瘍細胞が死滅することを明らかにしたことから，CREB3L1がMPNsにおける新たな診断マーカーや治療標的ともなり得るため，臨床的にも非常に価値があると考えられる。

Research Products

• [Journal Article] Non-driver gene mutation analysis in a large cohort of polycythemia vera and essential thrombocythemia (2023)
  • Author(s): Morishita S, Hashimoto Y, Furuya C, Edahiro Y, Ochiai T, Shirane S, Inano T, Yasuda H, Ando M, Araki M, Komatsu N
  • Journal Title: European Journal of Haematology Volume: 110 Issue: 2 Pages: 131-136
  • DOI: 10.1111/ejh.13882
  • Peer Reviewed
• [Journal Article] Reevaluation of cardiovascular risk factors for thrombotic events in 580 Japanese patients with essential thrombocythemia (2023)
  • Author(s): Furuya C, Hashimoto Y, Morishita S, Inano T, Ochiai T, Shirane S, Edahiro Y, Araki M, Ando M, Komatsu N
  • Journal Title: Journal of Thrombosis and Thrombolysis Volume: 55 Pages: 263-272
  • Peer Reviewed
• [Journal Article] Clinical and biological relevance of CREB3L1 in Philadelphia chromosome-negative myeloproliferative neoplasms (2022)
  • Author(s): De Marchi Federico、Okuda Maho、Morishita Soji、Imai Misa、Baba Terumi、Horino Mei、Mori Yosuke、Furuya Chiho、Ogata Satoko、Yang Yinjie、Ando Jun、Ando Miki、Araki Marito、Komatsu Norio
  • Journal Title: Leukemia Research Volume: 119 Pages: 106883-106883
  • DOI: 10.1016/j.leukres.2022.106883
  • Peer Reviewed
• [Journal Article] Clinical features of acquired erythrocytosis: Low levels of serum erythropoietin in a subset of non‐neoplastic erythrocytosis patients (2022)
  • Author(s): Mori Yosuke、Araki Marito、Morishita Soji、Imai Misa、Edahiro Yoko、Ito Masafumi、Ochiai Tomonori、Shirane Shuichi、Hashimoto Yoshinori、Yasuda Hajime、Ando Jun、Ando Miki、Komatsu Norio
  • Journal Title: Cancer Medicine Volume: 12 Issue: 2 Pages: 1079-1089
  • DOI: 10.1002/cam4.4958
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosis of essential thrombocythemia (2021)
  • Author(s): OCHIAI Tomonori、MORISHITA Soji、KOMATSU Norio
  • Journal Title: Japanese Journal of Thrombosis and Hemostasis Volume: 32 Issue: 4 Pages: 370-375
  • DOI: 10.2491/jjsth.32.370
  • NAID: 130008080837
  • ISSN: 0915-7441, 1880-8808
• [Journal Article] CREB3L1 overexpression as a potential diagnostic marker of Philadelphia chromosome?negative myeloproliferative neoplasms (2020)
  • Author(s): Morishita Soji、Yasuda Hajime、Yamawaki Saya、Kawaji Hideya、Itoh Masayoshi、Edahiro Yoko、Imai Misa、Kogo Yasushi、Tsuneda Satoshi、Ohsaka Akimichi、Hayashizaki Yoshihide、Ito Masafumi、Araki Marito、Komatsu Norio
  • Journal Title: Cancer Science Volume: 112 Issue: 2 Pages: 884-892
  • DOI: 10.1111/cas.14763
  • Peer Reviewed / Open Access
• [Presentation] Clinical relevance of CREB3L1 expression in Ph-negative MPN (2022)
  • Author(s): Soji Morishita, Federico De Marchi, Maho Okuda, Misa Imai, Terumi Baba, Yosuke Mori, Chiho Furuya, Satoko Ogata, Yinjie Yang, Jun Ando, Miki Ando, Marito Araki, Norio Komatsu
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Hypertriglyceridemia is a strong risk factor for thrombosis in ET patients (2022)
  • Author(s): Chiho Furuya, Yoshinori Hashimoto, Soji Morishita, Miki Ando, Norio Komatsu
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] The MPL mutation is a risk factor for thrombosis in addition to JAK2V617F mutation in ET patients (2022)
  • Author(s): Chiho Furuya, Yoshinori Hashimoto, Soji Morishita, Miki Ando, Norio Komatsu
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] 本態性血小板血症合併妊娠の管理 (2022)
  • Author(s): 小松則夫
  • Organizer: 第32回日本産婦人科・新生児血液学会
  • Invited
• [Presentation] Specific expression of CREB3L1 in megakaryocyte in myeloproliferative neoplasms (2021)
  • Author(s): Okuda M，Araki M，Federico D，Morishita S，Imai M，Mori Y，Horino M，Ochiai T，Shirame S，Edahiro Y，Ando J，Komatsu N
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] CREB3L1 Overexpresion Can Reliably Discriminate Ph-MPNs From Reactive Cases (2020)
  • Author(s): Soji Morishita, Hajime Yasuda, Saya Yamawaki, Hideya Kawaji, Masayoshi Itoh, Yoko Edahiro, Misa Imai, Yasushi Kogo, Satoshi Tsuneda, Akimichi Ohsaka, Yoshihide Hayashizaki, Marito Araki, and Norio Komatsu
  • Organizer: The 63rd American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] CREB3L1 overexpression as a novel diagnostic marker of Philadelphia-negative myeloproliferative neoplasms (2020)
  • Author(s): Soji Morishita, Hajime Yasuda, Saya Yamawaki, Hideya Kawaji, Masayoshi Itoh, Yoko Edahiro, Misa Imai, Yasushi Kogo, Satoshi Tsuneda, Akimichi Ohsaka, Yoshihide Hayashizaki, Marito Araki, and Norio Komatsu
  • Organizer: The 82nd Annual Meeting of Japanese Society of Hematology