Gene mutations in hematopoietic stem cells of chronic lymphocytic leukemia

• Project/Area Number: 24659462
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: MIYAMOTO TOSHIHIRO 九州大学, 大学病院, 講師 (70343324)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 慢性リンパ性白血病 / 造血幹細胞 / 白血化機構 / 幹細胞 / 白血病モデルマウス / エキソンシーケンス / 白血化

Outline of Final Research Achievements

Chronic lymphocytic leukemia (CLL) is a mature B cell malignancy, which has been considered to originate from mature B cells. We reported that even in CLL, very primitive hematopoietic stem cells (HSCs) should be involved in the pathogenesis of CLL. In this study, we tried to identify the somatic mutations acquired in primary CLL cells, and test whether such somatic mutations could be detected within HSCs of the CLL patients. We found that some of the identical somatic mutations acquired in CLL cells could be traced back to CD34+ human hematopoietic stem progenitor cells (HSPCs) and myeloid cells of the CLL patients. These results collectively suggest that early mutations associated with CLL pathogenesis should be acquired and accumulated within the self-renewing HSCs in human, and these abnormal pre-leukemic HSCs play a significant role in the multi-step leukemia progression processes of CLL.

Research Products

• [Journal Article] α-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice. (2015)
  • Author(s): Uryu H, Hashimoto D, Kato K, Hayase E, Matsuoka S, Ogasawara R, Takahashi S, Maeda Y, Iwasaki H, Miyamoto T, Saijo S, Iwakura Y, Hill GR, Akashi K, Teshima T
  • Journal Title: Blood Volume: 未定
  • Peer Reviewed
• [Journal Article] Pre-malignant lymphoid cells arise from hematopoietic stem/progenitor cells in chronic lymphocytic leukemia. (2015)
  • Author(s): Kikushige Y, Miyamoto T
  • Journal Title: Int J Hematol Volume: 未定
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CD41 marks the initial myelo-erythroid lineage specification in adult mouse hematopoiesis: redefinition of murine common myeloid progenitor. (2015)
  • Author(s): Miyawaki K, Arinobu Y, Iwasaki H, Kohno K, Tsuzuki H, Iino T, Shima T, Kikushige Y, Takenaka K, Miyamoto T, Akashi K.
  • Journal Title: Stem Cells Volume: 33 Issue: 3 Pages: 976-87
  • DOI: 10.1002/stem.1906
  • Peer Reviewed
• [Journal Article] Characteristics of patients with development of large granular lymphocyte expansion among dasatinib-treated patients with relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic stem cell transplantation. (2015)
  • Author(s): Ito Y, Miyamoto T, Kamimura T, Aoki K, Henzan H, Aoki T, Shiratsuchi M, Kato K, Nagafuji K, Ogawa R, Eto T, Iwasaki H, Akashi K.
  • Journal Title: Clin Lymphoma Myeloma Leuk. Volume: 15 Issue: 3 Pages: 47-54
  • DOI: 10.1016/j.clml.2014.09.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell. (2014)
  • Author(s): Shima T, Miyamoto T, Kikushige Y, Yuda J, Tochigi T, Yoshimoto G, Kato K, Takenaka K, Iwasaki H, Mizuno S, Goto N, Akashi K.
  • Journal Title: Exp. Hematol. Volume: 42 Issue: 11 Pages: 955-65
  • DOI: 10.1016/j.exphem.2014.07.267
  • Peer Reviewed / Open Access
• [Journal Article] Hematopoietic stem cell aging and chronic lymphocytic leukemia pathogenesis. (2014)
  • Author(s): Kikushige Y, Miyamoto T
  • Journal Title: Int J Hematol Volume: 100 Issue: 4 Pages: 335-340
  • DOI: 10.1007/s12185-014-1651-6
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Combination of bortezomib, thalidomide, and dexamethasone (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. (2014)
  • Author(s): Takashima S, Miyamoto T, Kadowaki M, Ito Y, Aoki T, Takase K, Shima T, Yoshimoto G, Kato K, Muta T, Shiratsuchi M, Takenaka K, Iwasaki H, Teshima T, Kamimura T, Akashi K.
  • Journal Title: Int J Hematol Volume: 100 Issue: 2 Pages: 159-164
  • DOI: 10.1007/s12185-014-1611-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Quantification of hematogones at the time of engraftment is a useful prognostic indicator in allogeneic stem cell transplantation. (2013)
  • Author(s): Shima T
  • Journal Title: Blood Volume: 121 Issue: 5 Pages: 840-848
  • DOI: 10.1182/blood-2012-02-409607
  • Peer Reviewed
• [Journal Article] Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment. (2013)
  • Author(s): Yamauchi T
  • Journal Title: Blood Volume: 121 Issue: 8 Pages: 1316-1325
  • DOI: 10.1182/blood-2012-06-440354
  • Peer Reviewed
• [Journal Article] Detection of minimal residual disease in patients with multiple myeloma using clonotype-specific PCR primers designed from DNA extracted from archival bone marrow slides. (2013)
  • Author(s): Takamatsu H, Ogawa Y, Kobayashi N, Obata K, Narisawa T, Nakayama K, Munemoto S, Aoki G, Ohata K, Kumano Y, Ozaki J, Murata R, Kondo Y, Terasaki Y, Kurokawa T, Miyamoto T, Shimizu N, Fukushima T, Yoshida A, Ueda T, Yoshida T, Nakao S
  • Journal Title: Exp Hematol Volume: 41 Issue: 10 Pages: 894-902
  • DOI: 10.1016/j.exphem.2013.05.004
  • Peer Reviewed
• [Journal Article] Evaluating the association between histological manifestations of cord colitis syndrome with GVHD. (2013)
  • Author(s): Shimoji S, Kato K, Eriguchi Y, Takenaka K, Iwasaki H, Miyamoto T, Oda Y, Akashi K, Teshima T
  • Journal Title: Bone Marrow Transplant Volume: 48 Issue: 9 Pages: 1249-1252
  • DOI: 10.1038/bmt.2013.44
  • Peer Reviewed
• [Journal Article] Combination of high-dose melphalan and bortezomib as conditioning regimen for autologous peripheral blood stem cell transplantation in multiple myeloma. (2013)
  • Author(s): Miyamoto T, Yoshimoto G, Kamimura T, Muta T, Takashima S, Ito Y, Shiratsuchi M, Choi I, Kato K, Takenaka K, Iwasaki H, Takamatsu Y, Teshima T, Akashi K.
  • Journal Title: Int J Hematol Volume: 98 Issue: 3 Pages: 337-345
  • DOI: 10.1007/s12185-013-1402-0
  • Peer Reviewed
• [Presentation] 造血器腫瘍における治療選択と臨床検査 (2014)
  • Author(s): 宮本敏浩
  • Organizer: 日本臨床検査医学会学術集会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-11-25
  • Invited
• [Presentation] 骨髄増殖性腫瘍の治療 (2014)
  • Author(s): 宮本敏浩
  • Organizer: 日本血液学会総会
  • Place of Presentation: 大阪市
  • Year and Date: 2014-11-05
  • Invited
• [Presentation] AML stem cells (2013)
  • Author(s): 宮本敏浩
  • Organizer: 第75回日本血液学会総会
  • Place of Presentation: 北海道札幌市
  • Invited
• [Presentation] 造血幹細胞移植前治療のUpdate (2013)
  • Author(s): 宮本敏浩
  • Organizer: 第75回日本血液学会総会
  • Place of Presentation: 北海道札幌市
• [Book] 白血病診療Q&A 一つ上を行く診療の実践 (2015)
  • Author(s): 宮本敏浩
  • Total Pages: 10
  • Publisher: 中外医学社
• [Book] 血液疾患最新の治療 2014-2016 (2014)
  • Author(s): 吉本五一、宮本敏浩
  • Total Pages: 7
  • Publisher: 南江堂
• [Book] Patient Surveillance After Cancer Treatment (2013)
  • Author(s): Miyamoto T
  • Total Pages: 538
  • Publisher: Humana Press
• [Book] Annual Review 血液 2013 (2013)
  • Author(s): 菊繁吉謙、宮本敏浩，赤司浩一
  • Total Pages: 9
  • Publisher: 中外医学社
• [Remarks] 九州大学第一内科ホームページ
  • URL: http://www.1nai.med.kyushu-u.ac.jp
• [Remarks] 九州大学医学部第一内科ホームページ
  • URL: http://www.1nai.med.kyushu-u.ac.jp