Molecular mechanisms of disease progression in myeloproliferative neoplasms.

• Project/Area Number: 24591401
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Miyazaki
• Principal Investigator: KITANAKA Akira 宮崎大学, 医学部, 准教授 (70343308)
• Co-Investigator(Kenkyū-buntansha): SHIMODA Kazuya 宮崎大学, 医学部, 教授 (90311844)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 骨髄増殖性腫瘍 / JAK2 / TET2 / MPN / TET / AML

Outline of Final Research Achievements

We examined the effects of JAK2 and TET2 mutations on myeloproliferative neoplasms (MPNs) development and disease progression. Recipients of JAK2V617F cells developed primary myelofibrosis-like features. The addition of TET2-loss worsened this phenotype. Double-mutant (JAK2V617F plus TET2-loss) myeloid cells were more likely to be in a proliferative state than JAK2V617F single-mutant cells. In a serial competitive transplantation assay, JAK2V617F cells resulted in decreased chimerism in the second recipients, which did not develop MPNs. In marked contrast, cooperation between JAK2V617F and TET2-loss developed and maintained MPNs in the second recipients. In-vitro sequential colony formation assays also supported the observation. We conclude that loss of TET2 has two different roles in MPNs: disease accelerator and disease initiator and sustainer in combination with JAK2V617F.

Research Products

• [Journal Article] Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator. (2015)
  • Author(s): Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Taniguchi Y, Hidaka T, Kubuki Y, Shimoda H, Marutsuka K, Sashida G, Aoyama K, Yoshimitsu M, Harada T, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K.
  • Journal Title: Blood Volume: 125 Issue: 2 Pages: 304-315
  • DOI: 10.1182/blood-2014-04-555508
  • NAID: 40020613861
  • Peer Reviewed / Open Access
• [Journal Article] Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes. (2015)
  • Author(s): Izumi K, Mine K, Inoue Y, Teshima M, Ogawa S, Kai Y, Kurafuji T, Hirakawa K, Miyakawa D, Ikeda H, Inada A, Hara M, Yamada H, Akashi K, Niho Y, Ina K, Kobayashi T, Yoshikai Y, Anzai K, Yamashita T, Minagawa H, Fujimoto S, Kurisaki H, Shimoda K, Katsuta H, Nagafuchi S.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 1-10
  • DOI: 10.1038/ncomms7748
  • Peer Reviewed / Open Access
• [Journal Article] Myelodysplastic syndrome with extramedullary erythroid hyperplasia induced by loss of Tet2 in mice. (2015)
  • Author(s): Muto T, Sashida G, Hasegawa N, Nakaseko C, Yokote K, Shimoda K, Iwama A.
  • Journal Title: Leuk Lymphoma. Volume: 56 Issue: 2 Pages: 520-523
  • DOI: 10.3109/10428194.2014.924120
  • Peer Reviewed / Open Access
• [Journal Article] Tyk2-Dependent Bystander Activation of Conventional and Nonconventional Th1 Cell Subsets Contributes to Innate Host Defense against Listeria monocytogenes Infection. (2014)
  • Author(s): Hashiguchi T, Oyamada A, Sakuraba K, Shimoda K, Nakayama KI, Iwamoto Y, Yoshikai Y, Yamada H.
  • Journal Title: J Immunol. Volume: 192 Issue: 10 Pages: 4739-4747
  • DOI: 10.4049/jimmunol.1303067
  • Peer Reviewed
• [Journal Article] Cbl negatively regulates erythropoietin-induced growth and survival signaling through the proteasomal degradation of Src kinase. (2014)
  • Author(s): Shintani T, Ohara-Waki F, Kitanaka A, Tanaka T, Kubota Y
  • Journal Title: Blood Cells Mol Dis. Volume: 53 Issue: 4 Pages: 211-218
  • DOI: 10.1016/j.bcmd.2014.06.005
  • Peer Reviewed
• [Journal Article] 骨髄増殖性腫瘍に対するJAK阻害剤の効果 (2014)
  • Author(s): 北中 明, 下田 和哉
  • Journal Title: 血液内科 Volume: 69 Pages: 423-428
  • NAID: 40020207852
• [Journal Article] 本邦における原発性骨髄線維症の臨床像 (2014)
  • Author(s): 下田 和哉, 竹中 克斗, 北中 明, 赤司 浩一
  • Journal Title: 臨床血液 Volume: 55 Pages: 289-294
  • NAID: 130004724847
• [Journal Article] クローン性検査の方法 遺伝子解析 JAK2変異を中心に (2014)
  • Author(s): 北中 明, 幣 光太郎, 下田 和哉
  • Journal Title: 血液フロンティア Volume: 24 Pages: 833-839
• [Journal Article] 骨髄増殖性腫瘍の分子機構と新規薬物療法 (2013)
  • Author(s): 北中 明, 幣 光太郎, 下田 和哉
  • Journal Title: 臨床血液 Volume: 54 Pages: 1697-1703
  • NAID: 10031196313
• [Journal Article] Effect of L-thyroxine replacement on apolipoprotein B-48 in overt and subclinical hypothyroid patients. (2013)
  • Author(s): Ito M, Kitanaka A, Arishima T, Kudo T, Nishihara E, Kubota S, Amino N, Hiraiwa T, Hanafusa T, Miyauchi A
  • Journal Title: Endocr J. Volume: 60 Pages: 65-71
  • NAID: 10031156724
  • Peer Reviewed
• [Journal Article] TET2 is essential for survival and hematopoietic stem cell homeostasis (2012)
  • Author(s): 幣光太郎
  • Journal Title: Leukemia Volume: (印刷中) Issue: 10 Pages: 2216-2223
  • DOI: 10.1038/leu.2012.94
  • Peer Reviewed
• [Journal Article] T-cell immunotherapy with a chimeric receptor against CD38 is effective in eradicating chemotherapy-resistant B-cell lymphoma cells overexpressing survivin induced by BMI-1. (2012)
  • Author(s): Bhattacharyya J, Mihara K, Kitanaka A, Yanagihara K, Kubo T, Takei Y, Kimura A, Takihara Y.
  • Journal Title: Blood Cancer Journal Volume: 2 Issue: 6 Pages: e75-e75
  • DOI: 10.1038/bcj.2012.21
  • Peer Reviewed
• [Journal Article] Acute myeloid leukemia in clinical practice: a retrospective population-based cohort study in Miyazaki Prefecture, Japan. (2012)
  • Author(s): Matsunaga T, Yamashita K, Kubuki Y, Toyama T, Imataki O, Maeda K, Kawano N, Satou S, Kawano H, Shimoda K, 他17名
  • Journal Title: Int J Hematol Volume: 96 Issue: 3 Pages: 342-349
  • DOI: 10.1007/s12185-012-1146-2
  • NAID: 10031121262
  • Peer Reviewed
• [Journal Article] Linezolid-induced pure red cell aplasia in a patient with Staphylococcus epidermidis infection after allogeneic stem cell transplantation. (2012)
  • Author(s): Waki F, Ohnishi H, Shintani T, Uemura M, Matsumoto K, Fukumoto T, Kitanaka A, Kubota Y, Tanaka T, Ishida T, Matsunaga T
  • Journal Title: Transpl Infect Dis. Volume: 14 Issue: 4
  • DOI: 10.1111/j.1399-3062.2012.00728.x
  • Peer Reviewed
• [Presentation] Therapies targeting the MAPK pathway improve bone marrow (BM) fibrosis induced by JAK2V617F. (2014)
  • Author(s): Shide K, Kameda T, Shimoda H, Kamiunten A ,Sekine M, Hidaka T, Kubuki Y, Kitanaka A, Shimoda K
  • Organizer: 第56回 ASH Annual Meeting and Exposition
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Ezh2 loss accelerates JAK2V617F-driven primary myelofibrosis. (2014)
  • Author(s): Sashida G,Tomioka T, Wang C, Shide K, Shimoda K, Iwama A
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] CALR mutation and clinical correlates in myeloproliferative neoplasms． (2014)
  • Author(s): Shide K, Kameda T, Kamiunten A ,Sekine M, Akizuki K, Shimoda H, Hidaka T, Kubuki Y, Kitanaka A, Shimoda
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Genetic and epigenetic abnormalities in myeloproliferative neoplasmas. (2014)
  • Author(s): Shimoda K
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
  • Invited
• [Presentation] Assessment of anti-pseudomonal beta-lactams as empirical treatment for febrile neutropnenia. (2014)
  • Author(s): Hidaka T, Kitanaka A, Akizuki K, Kamiunten A, Sekine M, Kameda T, Shide K, Shimoda H, Kubuki Y, Shimoda K.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 骨髄の線維化とその治療 (2014)
  • Author(s): 下田和哉
  • Organizer: 第111回日本内科学会講演会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-11 – 2014-04-13
  • Invited
• [Presentation] TET2 is essential for survival and hematopoietic stem cell homeostasis. (2012)
  • Author(s): Shide K, Kameda T,Shimoda H,Kamiunten A,Sekine M,Hidaka T,Kubuki Y, Marutsuka K, Iwama T,Kitanaka A, Shimoda K
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Cooperation of JAK2V617F and CBFb-MYH11 is insufficient for leukemic transformation of mouse MPNs. (2012)
  • Author(s): Kameda T, Shide K, Shimoda H, Kamiunten A, Hidaka T, Katayose K, Kubuki Y, Kitanaka A, Shimoda K, Marutsuka K
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Development of new therapies for myelofibrosis(MF) that target the transcription factor USF1
  • Author(s): 幣 光太郎, 亀田 拓郎, 下田 晴子, 上運天 綾子, 関根 雅明 , 日高 智徳, 久冨木 庸子, 北中 明, 下田 和哉
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 札幌
• [Presentation] The impact of TET2 deficiency on MPN induced by JAK2V617F mutation
  • Author(s): 亀田 拓郎, 幣 光太郎, 関根 雅明, 上運天 綾子, 日高 智徳, 久冨木 庸子, 北中 明, 下田 和哉, 丸塚 浩助
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 札幌
• [Presentation] Impact Of TET2 Deficiency On MPN Harboring JAK2V617F Mutation
  • Author(s): Kameda T, Shide K, Sekine M, Kamiunten A, Hidaka T, Kubuki Y, Kitanaka A, Marutsuka K, Shimoda K
  • Organizer: American Society of Hematology 55th Annual Meeting
  • Place of Presentation: New Orleans
• [Book] EBM血液疾患の治療 2015-2016 (2014)
  • Author(s): 関根雅明，下田和哉
  • Total Pages: 555
  • Publisher: 中外医学社
• [Book] 血液症候群(第2版)-その他の血液疾患を含めて- (2013)
  • Author(s): 北中 明, 下田 和哉
  • Total Pages: 767
  • Publisher: 日本臨床
• [Book] 原発性骨髄線維症の病因・病態と治療 (2012)
  • Author(s): 北中 明、下田和哉
  • Publisher: 日本臨牀社
• [Book] 骨髄線維症の外来管理 : どのような場合に入院を要するか (2012)
  • Author(s): 北中 明、下田和哉
  • Publisher: 科学評論社
• [Book] 骨髄線維症の病因と病態 (2012)
  • Author(s): 北中 明、下田和哉
  • Publisher: 日本内科学会
• [Book] 骨髄線維症に対する新規治療薬 (2012)
  • Author(s): 北中 明、下田和哉
  • Publisher: 中外医学社