Identification of a new transcriptional cascade activated by oncogenic JAK2 tyrosine kinase mutant

• Project/Area Number: 15K19559
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Juntendo University
• Principal Investigator: EDAHIRO YOKO 順天堂大学, 医学部, 助教 (40732863)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 骨髄増殖性腫瘍 / JAK2V617F / JAK2V617F変異

Outline of Final Research Achievements

JAK2V617F, a gain-of-function mutation in the tyrosine kinase JAK2, is frequently detected in myeloproliferative neoplasms (MPN), however its molecular mechanism in terms of MPN development is not fully understood. The identification of the JAK2 mutation in MPN led to the development of JAK2 inhibitors, however, treatment with these inhibitors is associated with side effects caused by blockade of function of wild-type JAK2; therefore, a new therapeutic strategy based on understanding of MPN development is required.
In this study, I found that AP-1 activation by JAK2V617F through c-FOS induction involves an unidentified molecular mechanism suggesting that deregulation of AP-1 plays a role in MPN development. Additionally, the AP-1 reporter assay system I have established should be useful not only for screening novel compounds for MPN treatment but also in studying the novel pathway regulated by JAK2V617F, which would lead to the development of a novel therapeutic strategy against MPN.

Research Products

• [Journal Article] utational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms. (2018)
  • Author(s): 3.Misawa K, Yasuda H, Araki M, Ochiai T, Morishita S, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
  • Journal Title: International journal of hematology Volume: -
  • Peer Reviewed
• [Journal Article] The 2014 BCSH criteria and the 2016 WHO criteria for essential thrombocythemia: A comparison in a large-scale cohort. (2018)
  • Author(s): Ochiai T, Yasuda H, Araki M, Misawa K, Morishita S, Nudejima M, Hironaka Y, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
  • Journal Title: Eur J Haematol Volume: 印刷中 Issue: 6 Pages: 544-549
  • DOI: 10.1111/ejh.13041
  • Peer Reviewed
• [Journal Article] The 2016 WHO diagnostic criteria for polycythemia vera renders an accurate diagnosis to a broader range of patients including masked polycythemia vera: Comparison with the 2008 WHO diagnostic criteria. (2017)
  • Author(s): Misawa K, Yasuda H, Araki M, Ochiai T, Morishita S, Nudejima M, Hironaka Y, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
  • Journal Title: Am J Hematol Volume: 92 Issue: 7
  • DOI: 10.1002/ajh.24752
  • Peer Reviewed
• [Journal Article] 本態性血小板血症治療の現状と今後 (2017)
  • Author(s): 枝廣陽子、小松則夫.
  • Journal Title: 血液フロンティア Volume: 1 Pages: 134-140
• [Journal Article] Co-occurrence of hyperleukocytosis and elevated fibrin-fibrinogen degradation product levels is a risk factor for early intracranial hemorrhage in patients with de novo acute leukemia. (2016)
  • Author(s): Ichikawa K, Edahiro Y, Gotoh A, Iiduka K, Komatsu N, Koike M.
  • Journal Title: Int J Hematol. Volume: 104 Issue: 5 Pages: 612-620
  • DOI: 10.1007/s12185-016-2072-5
  • Peer Reviewed
• [Journal Article] Safe and effective induction therapy with CHASER for primary testicular lymphoma with central nervous system involvement. (2016)
  • Author(s): Sunami Y, Ichikawa K, Edahiro Y, Komatsu N, Koike M.
  • Journal Title: Int J Clin Exp Med Volume: 9 Pages: 18645-18649
  • Peer Reviewed
• [Journal Article] Hydroxycarbamide投与中に急激な胸水貯留を来した骨髄線維化を伴う慢性骨髄単球性白血病. (2016)
  • Author(s): 角南 義孝、後藤 明彦、渡邊 直紀、枝廣 陽子、浜埜 康晴、原田 浩徳、小松 則夫.
  • Journal Title: 癌と化学療法 Volume: 43 Pages: 1223-1226
• [Journal Article] Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms. (2016)
  • Author(s): Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, Mizukami Y, Kan S, Shirane S, Edahiro Y, Sunami Y, Ohsaka A, Komatsu N
  • Journal Title: Blood Volume: 127 Issue: 10 Pages: 1307-16
  • DOI: 10.1182/blood-2015-09-671172
  • Peer Reviewed / Open Access
• [Journal Article] Identification of AIM2 as a downstream target of JAK2V617F. (2016)
  • Author(s): Liew EL, Araki M, Hironaka Y, Mori S, Tan TZ, Morishita S, Edahiro Y, Ohsaka A, Komatsu N.
  • Journal Title: Exp Hematol Oncol. Volume: 5 Issue: 1 Pages: 2-2
  • DOI: 10.1186/s40164-016-0032-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Application of genetic data to clinical practice of MPN (2015)
  • Author(s): Edahiro Y
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 8 Pages: 949-955
  • DOI: 10.11406/rinketsu.56.949
  • NAID: 130005096294
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] Current problems in the diagnosis of Philadelphia-negative myeloproliferative neoplasms in Japan (2015)
  • Author(s): 白根脩一、荒木真理人、森下総司、枝廣陽子、大阪顯通、小松則夫
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 7 Pages: 877-882
  • DOI: 10.11406/rinketsu.56.877
  • NAID: 130005093120
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Presentation] Localization of Mutant Calreticulin in the Golgi Apparatus Is Required for Its Oncogenic Capacity. 59th Annual Meeting of the American Society of Hematology. (2017)
  • Author(s): Nami Masubuchi, Marito Araki, Erina Hayashi, Yinjie Yang, Misa Imai, Yoshihiko Kihara, Yoshihisa Mizukami, Yumi Hironaka, Hiraku Takei, Yoko Edahiro, Akimichi Ohsaka, Norio Komatsu.
  • Organizer: 59th Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] ESTABLISHMENT OF AN IN VITRO MODEL FOR THE SKEWED MEGAKARYOPOIESIS BY CALRETICULIN MUTATION IN HUMAN CELLS (2017)
  • Author(s): Hiraku Takei, Shuichi Mano, Nami Masubuchi, Yoshihisa Mizukami, Soji Morishita, Misa Imai, Yoko Edahiro, Yumi Hironaka, Mai Nudejima, Satoshi Tsuneda, Hiroshi Endo, Sou Nakamura, Koji Eto, Akimichi Ohsaka, Marito Araki, Norio Komatsu.
  • Organizer: 22nd Congress of EHA
  • Int'l Joint Research
• [Presentation] 骨髄増殖性腫瘍に見出される変異型CALR 蛋白質の細胞内局在. (2017)
  • Author(s): 林英里奈、荒木真理人、増渕菜弥、水上喜久、楊印杰、今井美沙、弘中由美、竹井拓、木原慶彦枝廣陽子大坂顯通、小松則夫
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 変異型CALR タンパク質の発現を制御するメカニズム. (2017)
  • Author(s): 木原慶彦、荒木真理人、楊印杰、今井美沙、増渕菜弥、水上喜久、弘中由美、竹井拓、枝廣陽子、大坂顯通、小松則夫
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 変異型CALR による巨核球分化偏向性はGATA2の発現亢進と相関している. (2017)
  • Author(s): 竹井拓、眞野修一、増渕菜弥、水上喜久、今井美沙、森下総司、枝廣陽子、弘中由美、橳島麻衣、遠藤大、中村壮、江藤浩之、大坂顯通、荒木真理人、小松則夫
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Engagement of mutant calreticulin and MPL in acellular compartment is required for MPL activation. (2017)
  • Author(s): 増渕菜弥、荒木真理人、林英里奈、楊印杰、今井美沙、水上喜久、弘中由美、竹井拓、森下総司、木原慶彦、枝廣陽子、大坂顯通、小松則夫
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Modeling MPN phenotypes in vitro by using iPSC harboring CALR ins5 mutation. (2016)
  • Author(s): 竹井 拓、増渕 菜弥、眞野 修一、荒木 真理人、森下 総司、水上 喜久、カン シン、枝廣 陽子、角南 義孝、弘中 由美、遠藤 大、中村 壮、 江藤 浩之、大坂 顯通、小松 則夫.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 横浜、神奈川県、日本
  • Year and Date: 2016-10-13
• [Presentation] Mutant calreticulin activates the thrombopoietin receptor in myeloproliferative neoplasms (2016)
  • Author(s): 荒木 真理人、楊 印杰、増渕 菜弥、弘中 由美、竹井 拓、森下 総司、水上 喜久、カン シン、白根 脩一、枝廣 陽子、角南 義孝 、大坂 顯通、小松 則夫.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 横浜、神奈川県、日本
  • Year and Date: 2016-10-13
• [Presentation] Clinical characteristics of BCSH criteria defined PV and ET patients in Japan. (2016)
  • Author(s): 落合 友則、荒木 真理人、三澤 恭平、森下 総司、 橳島 麻衣、弘中 由美、白根 脩一、枝廣 陽子、角南 義孝、後藤 明彦、大坂 顯通、小松 則夫.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 横浜、神奈川県、日本
  • Year and Date: 2016-10-13
• [Presentation] Differential clinical features by subtypes of Calreticulin mutation in myeloproliferative neoplasms. (2016)
  • Author(s): 三澤 恭平、荒木 真理人、落合 友則、森下 総司、 橳島 麻衣、弘中 由美、白根 脩一、枝廣 陽子、角南 義孝、後藤 明彦、大坂 顯通、小松 則夫.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 横浜、神奈川県、日本
  • Year and Date: 2016-10-13
• [Presentation] Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms. (2016)
  • Author(s): Marito Araki, Yinjie Yang, Nami Masubuchi, Yumi Hironaka, Hiraku Takei, Soji Morishita, Yoshihisa Mizukami, Shin Kan, Shuichi Shirane, Yoko Edahiro, Yoshitaka Sunami, Akimichi Ohsaka, Norio Komatsu.
  • Organizer: 21st Congress of European Hematology Association
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2016-06-09
  • Int'l Joint Research
• [Presentation] Activation of AP-1 by JAK2V617F through induction and stabilization of c-Fos (2015)
  • Author(s): Edahiro Y, Araki M, Hironaka Y, Yang Y, Morishita Y, Sunami Y, Ohsaka A, Komatsu N
  • Organizer: 57th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Orlando FL, USA
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] A highly specific method for detecting a single copy JAK2V617F mutation (2015)
  • Author(s): Morishita S, Araki M, Hironaka Y, Sunami Y, Edahiro Y, Tsutsui M, Ohsaka A, Komatsu N
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢、石川県、日本
  • Year and Date: 2015-10-16
• [Presentation] Early disease onset of patients with triple-negative myeloproliferative neoplasms (2015)
  • Author(s): Shirane S, Araki M, Morishita S, Edahiro Y, Takei H, Tsumura M, Hironaka Y, Ochiai T, Misawa K, Ohsaka A, Komatsu N
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢、石川県、日本
  • Year and Date: 2015-10-16
• [Presentation] Establishment of iPS cells from myeloproliferative neoplasms patients with CALR mutation. (2015)
  • Author(s): Takei H, Morishita S, Araki M, Mizukami Y, Edahiro Y, Sunami Y, Hironaka Y, Tsumura M, Tsuneda S, Endo H, Nakamura S, Eto K, Ohsaka A, Komatsu N.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢、石川県、日本
  • Year and Date: 2015-10-16