Molecular mechanisms of blast crisis transition and maintenance of leukemic stem cells in chronic myelogenous leukemia

2010 Fiscal Year Final Research Report

• Project/Area Number: 22890043
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: NAKAHARA Fumio The University of Tokyo, 医科学研究所, 助教 (80581181)
• Project Period (FY): 2010
• Keywords: 白血病 / 白血病幹細胞 / 慢性骨髄性白血病 / 急性転化

Research Abstract

We show here that Hairy enhancer of split 1 (Hes1) has a role in blast crisis transition of CML. Hes1 is a basic helix-loop-helix transcriptional repressor that affects differentiation and often helps maintain cells in an immature state in various tissues. Also we show that expression of Hes1 immortalizes common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs). Whereas these cells did not develop myeloproliferative neoplasms when intravenously administered into irradiated mice, combination of Hes1 and BCR-ABL in both CMPs and GMPs caused a blast crisis of human CML-like disease, resulting in the rapid death of all the recipient mice. Intriguingly, Hes1 was highly expressed in 8 of 20 patients with CML in blast crisis, but not in the chronic phase, and dominant negative Hes1 retarded the growth of some CML cell lines expressing Hes1. These results taken together suggest that our model provides a good model to study mechanisms of the blast crisis transition in CML.

Research Products

• [Journal Article] Two types of C/EBPalpha mutations play distinct but collaborative roles in leukemogenesis : lessons from clinical data and BMT models. (2011)
  • Author(s): Kato N., J.Kitaura, N.Doki, Y.Komeno, N.Watanabe-Okochi, K.Togami, F.Nakahara, T.Oki, Y.Enomoto, Y.Fukuchi, H.Nakajima, Y.Harada, H.Harada, T.Kitamura
  • Journal Title: Blood 117 Pages: 221-233
• [Journal Article] One-year low-dose valacyclovir as prophylaxis for varicella zoster virus disease after allogeneic hematopoietic stem cell transplantation. A prospective study of the Japan Hematology and Oncology Clinical Study Group. (2010)
  • Author(s): Oshima K., T.Takahashi, T.Mori, T.Matsuyama, K.Usuki, Y.Asano-Mori, F.Nakahara, S.Okamoto, M.Kurokawa, Y.Kanda
  • Journal Title: Transpl Infect Dis 12 Pages: 421-427
• [Journal Article] AID-induced T-lymphoma or B-leukemia/lymphoma in a mouse BMT model. (2010)
  • Author(s): Komeno Y., J.Kitaura, N.Watanabe-Okochi, N.Kato, T.Oki, F.Nakahara, Y.Harada, H.Harada, R.Shinkura, H.Nagaoka, Y.Hayashi, T.Honjo, T.Kitamura
  • Journal Title: Leukemia 24 Pages: 1018-1024
• [Journal Article] Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia. (2010)
  • Author(s): Nakahara F., M.Sakata-Yanagimoto, Y.Komeno, N.Kato, T.Uchida, K.Haraguchi, K.Kumano, Y.Harada, H.Harada, J.Kitaura, S.Ogawa, M.Kurokawa, T.Kitamura, S.Chiba
  • Journal Title: Blood 115 Pages: 2872-2881
• [Presentation] Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myeloid leukemia. (2011)
  • Author(s): Fumio Nakahara, Toshio Kitamura, 他
  • Organizer: 日米血液腫瘍セミナー2011
  • Place of Presentation: 神奈川県葉山湘南国際村センター
  • Year and Date: 2011-02-26
• [Presentation] Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myeloid leukemia. (2011)
  • Author(s): Fumio Nakahara, Toshio Kitamura, 他
  • Organizer: 「個体レベルでのがん研究支援活動」ワークショップ
  • Place of Presentation: 滋賀県琵琶湖ホテル
  • Year and Date: 2011-02-03
• [Remarks] ホームページ等