Role of epigenetic regulation by nuclear tyrosine kinases in hematologic malignancies

• Project/Area Number: 26893036
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Chiba University
• Principal Investigator: Aoyama Kazumasa 千葉大学, 医学(系)研究科(研究院), 特任研究員 (50734266)
• Project Period (FY): 2014-08-29 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: エピジェネティックス / 癌 / チロシンキナーゼ / ヒストン修飾 / 遺伝子発現

Outline of Final Research Achievements

A constitutively active mutant of Abl tyrosine kinase causes chronic myelogenous leukemia (CML). In this study, we showed that Abl-mediated tyrosine phosphorylation leads to stabilization of histone deacetylase 1 accompanied by global histone deacetylations. Furthermore, we demonstrated that JAK2V617F, which is a constitutively active mutant of JAK2 tyrosine kinase and is found in patients with myeloproliferative neoplasms (MPN), cooperates with polycomb repressive complex2 in regulation of histone H3 lysine27 trimethylation. These results suggest that tyrosine kinases-regulated histone modifications plays an important role in CML and MPN.

Research Products

• [Journal Article] Gene expression profiling of loss of TET2 and/or JAK2V617F mutant hematopoietic stem cells from mouse models of myeloproliferative neoplasms. (2015)
  • Author(s): Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Hidaka T, Kubuki Y, Sashida G, Aoyama K, Yoshimitsu M, Abe H, Miike T, Iwakiri H, Tahara Y, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K
  • Journal Title: Genom Data. Volume: 4 Pages: 102-108
  • DOI: 10.1016/j.gdata.2015.04.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. (2015)
  • Author(s): Mochizuki-Kashio M, Aoyama K, Sashida G, Oshima M, Tomioka T, Muto T, Wang C, Iwama A.
  • Journal Title: Blood Volume: 126 Issue: 10 Pages: 1172-83
  • DOI: 10.1182/blood-2015-03-634428
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] c-Abl-mediated tyrosine phosphorylation of JunB is required for Adriamycin-induced expression of p21. (2015)
  • Author(s): Noritaka Yamaguchi, Ryuzaburo Yuki, Sho Kubota, Kazumasa Aoyama, Takahisa Kuga, Yuuki Hashimoto, Takeshi Tomonaga, and Naoto Yamaguchi.
  • Journal Title: Biochemical Journal Volume: 471 Issue: 1 Pages: 67-77
  • DOI: 10.1042/bj20150372
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Overexpression of Zinc-finger protein 777 (ZNF777) inhibits proliferation at low cell density through down-regulation of FAM129A. (2015)
  • Author(s): Yuki, R., Aoyama, K., Kubota, S., Yamaguchi, N.-t., Kubota, S.-i., Hasegawa, H., Morii, M., Huang, X., Liu, K., Williams, R., Fukuda, M.N., and Yamaguchi, N.
  • Journal Title: J. Cell. Biochem. Volume: in press Issue: 6 Pages: 954-968
  • DOI: 10.1002/jcb.25046
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] c-Abl induces stabilization of histone deacetylase 1 (HDAC1) in a kinase activity-dependent manner. (2015)
  • Author(s): Kazumasa Aoyama, Noritaka Yamaguchi, Ryuzaboro Yuki, Mariko Morii, Sho Kubota, Kensuke Hirata, Kohei Abe, Takuya Honda, Takahisa Kuga, Yuuki Hashimoto, Takeshi Tomonaga, and Naoto Yamaguchi
  • Journal Title: Cell Biology International Volume: 39 Issue: 4 Pages: 446-456
  • DOI: 10.1002/cbin.10413
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Role for Tyrosine Phosphorylation of A-kinase Anchoring Protein 8 (AKAP8) in its Dissociation from Chromatin and the Nuclear Matrix (2015)
  • Author(s): Kubota S, Morii M, Yuki R, Yamaguchi N, Yamaguchi H, Aoyama K, Kuga T, Tomonaga T, Yamaguchi N.
  • Journal Title: J Biol Chem Volume: 290 Issue: 17 Pages: 10891-904
  • DOI: 10.1074/jbc.m115.643882
  • Peer Reviewed / Open Access
• [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
• [Presentation] Role of Ezh1 in hematopoietic malignancies induced by Ezh2 insufficiency (2016)
  • Author(s): Kazumasa Aoyama, Makiko Mochizuki-Kashio, Motohiko Oshima, Shuhei Koide, Atsushi Iwama
  • Organizer: JSPS-NUS Joint Symposium
  • Place of Presentation: Singapore （Singapore）
  • Year and Date: 2016-01-14
  • Int'l Joint Research
• [Presentation] Role of histone methyltransferase Ezh1 in Ezh2-deficient hematopoietic stem cells (2015)
  • Author(s): Kazumasa Aoyama, Makiko Mochizuki-Kashio, Motohiko Oshima, Shuhei Koide, Goro Sashida, Atsushi Iwama
  • Organizer: 第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド（兵庫・神戸）
  • Year and Date: 2015-12-01