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

• Project/Area Number: 23791074
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: NAKAHARA Fumio 東京大学, 医科学研究所, 助教 (80581181)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 白血病 / 白血病幹細胞 / 慢性骨髄性白血病 / 急性転化

Research Abstract

High levels of Hes1 expression are frequently found in BCR-ABL-positive chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC-like disease; however the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-kB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of Hes1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, these CMPs secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC-like disease induced by BCR-ABL and Hes1 in mouse BMT models. Thus, Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.

Research Products

• [Journal Article] Human CD300C Delivers an Fc Receptor-gamma-dependent Activating Signal in Mast Cells and Monocytes and Differs from CD300A in Ligand Recognition (2013)
  • Author(s): Takahashi M, Izawa K, Kashiwakura J, Yamanishi Y, Enomoto Y, Kaitani A, Maehara A, Isobe M, Ito S, Matsukawa T, Nakahara F, Oki T, Kajikawa M, Ra C, Okayama Y, Kitamura T and Kitaura J
  • Journal Title: J Biol Chem Volume: 288 Pages: 7662-75
• [Journal Article] The receptor LMIR3 negatively regulates mast cell activation and allergic responses by binding to extracellular ceramide (2012)
  • Author(s): Izawa K, Yamanishi Y, Maehara A, Takahashi M, Isobe M, Ito S, Kaitani A, Matsukawa T, Matsuoka T, Nakahara F,Oki T, Kiyonari H, Abe T, Okumura K, Kitamura T and Kitaura J
  • Journal Title: Immunity Volume: 37 Pages: 827-39
• [Journal Article] Upregulation of CD200R1 in lineage-negative leukemic cells is characteristic of AML1-ETO-positive leukemia in mice (2012)
  • Author(s): Kagiyama Y, Kitaura J, Togami K, Uchida T, Inoue D, Matsukawa T, Izawa K, Kawabata KC, Komeno Y, Oki T, Nakahara F, Sato K, Aburatani H and Kitamura T
  • Journal Title: Int J Hematol Volume: 96 Pages: 638-48
  • NAID: 10031126762
• [Journal Article] Molecular mechanisms underlying leukemic transformation of myelodysplastic syndromes (MDS) and chronic myelogenous leukemia (CML) (2012)
  • Author(s): Kitamura T, Watanabe-Okochi N, InoueD, Togami K, Uchida T, Kagiyama Y, Kawabata K, Chiba S, Harada Y, Harada H, Kitaura J and Nakahara F
  • Journal Title: Rinsho Ketsueki Volume: 53 Pages: 734-9
  • NAID: 130004501712
• [Journal Article] A soluble form of LMIR5/CD300b amplifies lipopolysaccharide-induced lethal inflammation in sepsis (2012)
  • Author(s): Yamanishi Y, Takahashi M, Izawa K, Isobe M, Ito S, Tsuchiya A, Maehara A, Kaitani A, Uchida T, Togami K, Enomoto Y, Nakahara F, Oki T, Kajikawa M, Kurihara H, Kitamura T and Kitaura J
  • Journal Title: J Immuno Volume: l189 Pages: 1773-9
• [Journal Article] Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models (2012)
  • Author(s): Doki N, Kitaura J, Uchida T, Inoue D, Kagiyama Y, Togami K, Isobe M, Ito S, Maehara A, Izawa K, Kato N, Oki T, Harada Y, Nakahara F, Harada H and Kitamura T
  • Journal Title: Int JHematol Volume: 95 Pages: 167-75
  • NAID: 10030267340
• [Journal Article] Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis. (2012)
  • Author(s): Oki T, Kitaura J, Watanabe-Okochi N, Nishimura K, Maehara A, Uchida T, Komeno Y, Nakahara F, Harada Y, Sonoki T, Harada H and Kitamura T
  • Journal Title: Leukemia Volume: 26 Pages: 1038-45
• [Journal Article] Transforming growth factor-beta-stimulated clone-22 is a negative-feedback regulator of Ras / Raf signaling: Implications for tumorigenesis (2012)
  • Author(s): Nakamura M, Kitaura J, Enomoto Y, Lu Y, Nishimura K, Isobe M, Ozaki K, Komeno Y, Nakahara F, Oki T, Kume H, Homma Y and Kitamura T
  • Journal Title: Cancer Sci Volume: 103 Pages: 26-33
• [Journal Article] Identification of RHOXF2 (PEPP2) as a cancer-promoting gene by expression cloning (2012)
  • Author(s): Shibata-Minoshima F, Oki T, Doki N,Nakahara F, Kageyama S, Kitaura J, Fukuoka J and Kitamura T
  • Journal Title: Int J Oncol Volume: 40 Pages: 93-8
• [Journal Article] The receptor LMIR3 negatively regulates mast cell activation and allergic responses by binding to extracellular ceramide. (2012)
  • Author(s): Izawa K, Yamanishi Y, Maehara A, Takahashi M, Isobe M, Ito S, Kaitani A, Matsukawa T, Matsuoka T, Nakahara F, Oki T, Kiyonari H, Abe T, 0kumura K, Kitamura T, Kitaura J.
  • Journal Title: Immunity Volume: 16;37(5) Issue: 5 Pages: 827-39
  • DOI: 10.1016/j.immuni.2012.08.018
  • Peer Reviewed
• [Journal Article] Upregulation of CD200R1 in lineage-negative leukemic cells is characteristic of AML1-ETO-positive leukemia in mice. (2012)
  • Author(s): Kagiyama Y, Kitaura J, Togami K, Uchida T, Inoue D, Matsukawa T, Izawa K, Kawabata KC, Komeno Y, Oki T, Nakahara F, Sato K, Aburatani H, Kitamura T.
  • Journal Title: Int J Hematol. Volume: 96(5) Issue: 5 Pages: 638-48
  • DOI: 10.1007/s12185-012-1207-6
  • Peer Reviewed
• [Journal Article] Molecular mechanisms underlying leukemic transformation of myelodysplastic syndromes (MDS) and chronic myelogenous leukemia (CML) (2012)
  • Author(s): Kitamura T
  • Journal Title: Rinsho Ketsueki Volume: 53(8) Pages: 734-39
• [Journal Article] Fyn is not essential for Bcr-Ab1-induced leukemogenesis in mouse bone marrow transplantation models (2012)
  • Author(s): Doki N, Kitaura J, Inoue D, Kato N, Kagiyama Y, Uchida T, Togami K, Isobe M, Ito S, Maehara A, Izawa K, Oki T, Harada Y, Nakahara F, Harada H, Kitamura T
  • Journal Title: Int J Hematol Volume: 95(2) Issue: 2 Pages: 167-175
  • DOI: 10.1007/s12185-011-0994-5
  • Peer Reviewed
• [Journal Article] Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis (2012)
  • Author(s): Oki T, Kitaura J, Watanabe-Okochi N, Nishimura K, Maehara A, Uchida T, Komeno Y, Nakahara F, Harada Y, Sonoki T, Harada H, Kitamura T
  • Journal Title: Leukemia Volume: (in press) Issue: 5 Pages: 1038-1045
  • DOI: 10.1038/leu.2011.328
  • Peer Reviewed
• [Presentation] Molecular mechanisms of blast crisis in chronic myelogenous leukemia caused by upregulation of Hes1 (2012)
  • Author(s): Fumio Nakahara, Toshio Kitamura
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2012-10-20
• [Presentation] Molecular mechanisms of blast crisis in chronic (2011)
  • Author(s): 第70回日本癌学会学術総会
  • Organizer: 日本癌学会(招待講演)
  • Place of Presentation: 名古屋国際会議場