Role of Epigenomic alterations in Myeloproliferative neoplasms

• Project/Area Number: 19K17834
• 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 Miyazaki
• Principal Investigator: Kamiunten Ayako 宮崎大学, 医学部, 助教 (30800750)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: MPN / ET / myelofibrosis / CALR / EZH2 / TET2 / primary myelofibrosis / EZH / 骨髄増殖性腫瘍 / エピゲノム異常 / CALR変異

Outline of Research at the Start

骨髄増殖性腫瘍(myeloproliferative neoplasms: MPN) に分類される本態性血小板血症(essential thrombocythemia; ET)、原発性骨髄線維症(primary myelofibrosis; PMF)の症例で共通してみられるCalreticulin(CALR)変異やJAK2変異と、EZH2やTET2などのエピゲノム異常を併せ持つマウスモデルを作成する。表現型の違いや白血病への移行の頻度を解析し、MPNにおけるエピゲノム異常の役割やAMLへの急性転化の際の分子病態を明らかにする。

Outline of Final Research Achievements

We generated CALR mutant mice and CALR mutant/EZH2-deficient mice. Both developed ET, but did not develop myelofibrosis or leukemia, and their survival time was equivalent to that of wild type mice.
Next, We performed competitive transplantation with CALR mutant LSKs or CALR mutant/EZH2-deficient LSKs. Although none of them developed ET, we observed increased percentage of donor-derived cells the mice transplanted with CALR mutant LSK or CALR mutant/EZH2-deficient LSK. No difference in chimerism was observed between CALR mutant/EZH2-deficient LSK transplanted mice and CALR mutant LSK transplanted mice. We found that EZH2 deficiency for CALR mutations does not affect progression to MF or the differentiation potential of stem cells.

Academic Significance and Societal Importance of the Research Achievements

本研究により、骨髄増殖性腫瘍ではドライバー遺伝子の種類によってエピゲノム異常の与える影響が異なる事が明らかとなった。この結果により、CALR変異をもつ骨髄増殖性腫瘍の発症や急性転化に寄与するエピゲノム異常を同定し、新規治療薬の開発につながる事が期待できる。また、骨髄増殖性腫瘍患者のドライバー遺伝子やエピゲノム遺伝子変異の種類により予後の層別化を行い、新たな治療戦略の開発につながる事が期待される。

Research Products

• [Journal Article] Calreticulin haploinsufficiency augments stem cell activity and is required for onset of myeloproliferative neoplasms (2020)
  • Author(s): Shide Kotaro、Kameda Takuro、Kamiunten Ayako、Ozono Yoshinori、Tahira Yuki、Yokomizo-Nakano Takako、Kubota Sho、Ono Masaya、Ikeda Kazuhiko、Sekine Masaaki、Akizuki Keiichi、Nakamura Kenichi、Hidaka Tomonori、Kubuki Yoko、Iwakiri Hisayoshi、Hasuike Satoru、Nagata Kenji、Sashida Goro、Shimoda Kazuya
  • Journal Title: Blood Volume: - Pages: 106-118
  • DOI: 10.1182/blood.2019003358
  • Peer Reviewed / Open Access
• [Journal Article] Neoplastic fibrocytes play an essential role in bone marrow fibrosis in Jak2V617F-induced primary myelofibrosis mice (2020)
  • Author(s): Ozono Yoshinori、Shide Kotaro、Kameda Takuro、Kamiunten Ayako、Tahira Yuki、Sekine Masaaki、Akizuki Keiichi、Nakamura Kenichi、Iwakiri Hisayoshi、Sueta Mitsue、Hidaka Tomonori、Kubuki Yoko、Yamamoto Shojiro、Hasuike Satoru、Sawaguchi Akira、Nagata Kenji、Shimoda Kazuya
  • Journal Title: Leukemia Volume: - Issue: 2 Pages: 454-467
  • DOI: 10.1038/s41375-020-0880-3
  • Peer Reviewed / Open Access
• [Presentation] Loss of EZH2 does not affect the severity of murine myeloproliferative neoplasms with CALR mutation (2021)
  • Author(s): Ayako Kamiunten,Takuro Kameda, Yuki Tahira, Keiichi Akizuki, Masaaki Sekine, Kotaro shide,Tomonori Hidaka, Yoko Kubuki, Kazuya Shimoda
  • Organizer: The 83th Annual Meeting of the Japanese society of Hematology, OS2-7-3, Sendai Japan, Sep 24.2021(口演)
• [Presentation] RNA splicing machinery gene mutations in patients with myeloproliferative neoplasms (MPNs) in Japan (2021)
  • Author(s): Kotaro Shide, Saki Ogawa, Ayako Kamiunten et al
  • Organizer: The 83th Annual Meeting of the Japanese society of Hematology, OS2-7B-4, Sendai JAPAN, Sep 24.2021 (口演)
• [Presentation] Renal impairment associated with myeloproliferative neoplasm (MPN) (2021)
  • Author(s): Yuki Tahira, Kotaro Shide, Ayako Kamiunten, Takuro Kameda, Keiichi Akizuki, Masaaki Sekine, Tomonori Hidaka, Yoko Kubuki, Kazuya Shimoda
  • Organizer: The 83th Annual Meeting of the Japanese society of Hematology, PS-11-6, Sendai JAPAN, Sep 23.2021 (ポスター)
• [Presentation] Mechanism of enhanced IL1α production induced by JAK2V617F (2020)
  • Author(s): Kotaro shide, Ayako Kamiunten, Yoshinori Ozono, Takuro Kameda, Yuki Tahira, Keiichi Akizuki, Masaaki Sekine, Tomonori Hidaka, Yoko Kubuki, Kazuya Shimoda
  • Organizer: the 82th Annual Meeting of the Japanese society of Hematology, OS-25-5, Kyoto JAPAN(WEB開催), Oct 10.2020(口演)
• [Presentation] Myeloproliferative noplasm(MPN) nephropathy in Jak2V617F induced MPN mouse model (2020)
  • Author(s): Yuki Tahira, Kotaro shide, Yoshinori Ozono, Ayako Kamiunten, Takuro Kameda, Keiichi Akizuki, Masaaki Sekine, Tomonori Hidaka, Yoko Kubuki, Kazuya Shimoda
  • Organizer: the 82th Annual Meeting of the Japanese society of Hematology, PS-12-6, Kyoto JAPAN(WEB開催), Oct 10.2020(ポスター)