Pathological role of the dysregulated polycomb functions in hematological malignancies

• Project/Area Number: 15H02544
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Chiba University
• Principal Investigator: Iwama Atsushi 千葉大学, 大学院医学研究院, 教授 (70244126)
• Co-Investigator(Kenkyū-buntansha): 仁田 英里子 神戸大学, 医学研究科, 助教 (80401123)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥41,730,000 (Direct Cost: ¥32,100,000、Indirect Cost: ¥9,630,000); Fiscal Year 2017: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000); Fiscal Year 2016: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000); Fiscal Year 2015: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
• Keywords: 造血腫瘍 / エピジェネティクス / ポリコーム群複合体 / Pcgf1 / Kdm2b / 造血幹細胞 / 骨髄球分化 / 血液 / 骨髄増殖性腫瘍 / 造血器腫瘍 / ポリコーム群遺伝子 / Ezh1 / Ezh2 / 骨髄異形成症候群

Outline of Final Research Achievements

Polycomb-group (PcG) proteins catalyze repressive histone marks. Canonical polycomb repressive complex (PRC) 1 containing Pcgf4/Bmi1 has been implicated in the maintenance of hematopoietic stem cells (HSCs). We analyzed the role of non-canonical PRC1.1 consisting of Pcgf1, Kdm2b, Bcor and Ring1b using conditional knockout mice. We found that PRC1.1 was dispensable for self-renewal capacity of HSCs. Instead, PRC1.1 insufficiency enhanced commitment of hematopoietic stem and progenitor cells (HSPCs) to myeloid lineage and induced myeloid-biased differentiation, eventually leading to the development of lethal myeloproliferative neoplasm (MPN). Comprehensive analyses revealed that master transcriptional factor genes for myeloid differentiation, such as Cebpa, were up-regulated following a reduction in H2AK119ub1 levels in PRC1.1-insufficient HSPCs, resulting in the premature activation of their targets. These results indicate that PRC1.1 negatively regulates myeloid commitment of HSPCs.

Research Products

• [Int'l Joint Research] Minnesota 大学(米国)
• [Int'l Joint Research] Harvard Medical School(米国)
• [Int'l Joint Research] University of Singapore(Singapore)
• [Int'l Joint Research] シンガポール大学がん研究所(シンガポール)
• [Int'l Joint Research] ハーバード大学医学部(米国)
• [Journal Article] Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies (2017)
  • Author(s): Tanaka Tomoyuki、Nakajima-Takagi Yaeko、Aoyama Kazumasa、Tara Shiro、Oshima Motohiko、Saraya Atsunori、Koide Shuhei、Si Sha、Manabe Ichiro、Sanada Masashi、Nakayama Manabu、Masuko Masayoshi、Sone Hirohito、Koseki Haruhiko、Iwama Atsushi
  • Journal Title: The Journal of Experimental Medicine Volume: 214 Issue: 10 Pages: 2901-2913
  • DOI: 10.1084/jem.20170167
  • Peer Reviewed / Open Access
• [Journal Article] Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. (2017)
  • Author(s): Seki M, Kimura S, Isobe T, Yoshida K, (13 authors), Masuda K, Kawamoto H, Ohki K, Kato M, Arakawa Y, Koh K, Hanada R, Moritake H, Akiyama M, Kobayashi R, Deguchi T, Hashii Y, Imamura T, Sato A, Kiyokawa N, Oka A, Hayashi Y, Takagi M, Manabe A, Ohara A, Horibe K, Sanada M, Iwama A, Mano H, Miyano S, Ogawa S, Takita J
  • Journal Title: Nature Genetics Volume: 49 Issue: 8 Pages: 1274-1281
  • DOI: 10.1038/ng.3900
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Polycomb repressive complexes in hematological malignancies. (2017)
  • Author(s): Iwama A
  • Journal Title: Blood Volume: 130 Issue: 1 Pages: 23-29
  • DOI: 10.1182/blood-2017-02-739490
  • Peer Reviewed
• [Journal Article] Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome. (2016)
  • Author(s): Hasegawa N, Oshima M, Sashida G, Matsui H, Koide S, Saraya A, Wang C, Muto T, Takane K, Kaneda A, Shimoda K, Nakaseko C, Yokote K, Iwama A.
  • Journal Title: Leukemia Volume: in press Issue: 4 Pages: 861-871
  • DOI: 10.1038/leu.2016.268
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The loss of Ezh2 cooperates with an active JAK2 mutant in the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. (2016)
  • Author(s): Sashida G, Wang S, Tomioka T, Oshima M, Kazumasa Aoyama K, Kanai A, Mochizuki-Kashio M, Harada H, Shimoda K, Iwama A.
  • Journal Title: J Experimenta l Medicine Volume: 213 Issue: 8 Pages: 1459-1477
  • DOI: 10.1084/jem.20151121
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of non-hematopoietic genes. (2016)
  • Author(s): Koide S, Oshima M, Takubo K, Yamazaki S, Nitta E, Saraya A, Aoyama K, Kato Y, Miyagi S, Nakajima-Takagi Y, Chiba T, Matsui H, Arai F, Suzuki Y, Kimura H, Nakauchi H, Suda T, Shinkai Y,Iwama A.
  • Journal Title: Blood Volume: 128(5) Issue: 5 Pages: 638-649
  • DOI: 10.1182/blood-2016-01-694810
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ezh2 regulates the Lin28/let-7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells. (2016)
  • Author(s): Oshima M, Hasegawa N, Mochizuki-Kashio M, Muto T, Miyagi S, Koide S, Yabata S, Wendt G, Saraya A, Wang C, Shimoda K, Suzuki Y, Iwama A.
  • Journal Title: Exp Hematol Volume: 44 Pages: 282-296
  • Peer Reviewed / Acknowledgement Compliant
• [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, and Iwama A.
  • Journal Title: Blood Volume: 126 Pages: 1172-1183
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Non-lethal ionizing radiation promotes aging-like phenotypic changes of human hematopoietic stem and progenitor cells in humanized mice. (2015)
  • Author(s): Wang C, Oshima M, Gashida G, Tomioka T, Hasegawa N, Mochizuki-Kashio M, Nakajima-Takagi Y, Kusunoki Y, Kyoizumi S, Imai K, Nakachi K, and Iwama A.
  • Journal Title: Plos One Volume: 10(7)
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Ineffective erythropoiesis in myelodysplastic syndrome (2017)
  • Author(s): 岩間厚志
  • Organizer: 第79回日本血液学会学術集会
  • Invited
• [Presentation] 造血器腫瘍とエピジェネティクス (2017)
  • Author(s): 岩間厚志
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] ポリコーム群複合体による造血幹細胞のエピジェネティック制御 (2017)
  • Author(s): 岩間厚志
  • Organizer: 第65回 日本輸血・細胞治療学会総会
  • Invited
• [Presentation] 造血幹細胞のエピジェネティック制御 (2017)
  • Author(s): 岩間厚志
  • Organizer: 第27回 日本サイトメトリー学会学術集会
  • Invited
• [Presentation] Deregulated polycomb function in the pathogenesis of MDS (2016)
  • Author(s): Iwama A
  • Organizer: The 78th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Pacifico Yokohama, Yokohama, Kanagawa
  • Year and Date: 2016-10-13
  • Int'l Joint Research / Invited
• [Presentation] Deregulated polycomb-group gene functions in hematological malignancies (2016)
  • Author(s): Iwama A
  • Organizer: 5th JCA-AACR Special Joint Conference.
  • Place of Presentation: Tokyo bay Maihama Hotel Club Resort, Urayasu, Chiba
  • Year and Date: 2016-07-13
  • Int'l Joint Research / Invited
• [Presentation] Role of polycomb-group complexes in hematopoietic stem aging and disease (2016)
  • Author(s): Iwama A
  • Organizer: 1st International Symposium on Stem Cell Aging and Disease.
  • Place of Presentation: Ito Hall, the University of Tokyo,Tokyo
  • Year and Date: 2016-06-29
  • Int'l Joint Research / Invited
• [Presentation] Role of non-canonical polycomb repressive complex 1 in fate decision of hematopoietic stem cells. (2016)
  • Author(s): Iwama A
  • Organizer: Annual Meeting of International Society of Stem Cell Research
  • Place of Presentation: Moscone West, San Francisco,California, U.S.A.
  • Year and Date: 2016-06-22
  • Int'l Joint Research / Invited
• [Presentation] Polycomb repressive complexes in hematological malignancies (2016)
  • Author(s): Iwama A
  • Organizer: 11th International Workshop on Melecular aspects of myeloid stem cell development and leukemia.
  • Place of Presentation: Cincinnati Children’s Hospital Medical Center,Ohio,U.S.A.
  • Year and Date: 2016-05-02
  • Int'l Joint Research / Invited
• [Presentation] 造血幹細胞におけるバリアントＰＲＣ１複合体の機能 (2016)
  • Author(s): 岩間 厚志
  • Organizer: 第１５回日本再生医療学会総会
  • Place of Presentation: 大阪国際会議場,大阪府大阪市
  • Year and Date: 2016-03-17
  • Invited
• [Presentation] ヒストンメチル基転移酵素 Ezh2 欠損造血幹細胞における Ezh1 の役割 (2015)
  • Author(s): 青山 和正
  • Organizer: 第３８回日本分子生物学会年会
  • Place of Presentation: 神戸ポートタワーホテル、兵庫県神戸市
  • Year and Date: 2015-12-01
• [Presentation] EZH2 loss in Hemtpoietic Stem cells predisposes mice to develop heterogeneous hematological malignancies (2015)
  • Author(s): Mochizuki-Kashio Makiko
  • Organizer: The 13th International Symposium on Myelodysplastic Syndromes,
  • Place of Presentation: Washington D.C.、U.S.A.
  • Year and Date: 2015-04-29
  • Int'l Joint Research