ヒト疾患に近いシステムを用いた白血病発症におけるBCR-ABL1遺伝子の機能解析

2010 Fiscal Year Annual Research Report

• Project/Area Number: 21591200
• Research Institution: Mie University
• Principal Investigator: 片山 直之 三重大学, 大学院・医学系研究科, 教授 (20185812)
• Keywords: 血液腫瘍学 / 慢性骨髄性白血病 / 急性リンパ性白血病 / 造血幹細胞 / BCR-ABL1遺伝子 / Ikaros遺伝子 / ヒト骨髄由来ストローマ細胞 / リンパ球分化

Research Abstract

慢性骨髄性白血病(CML)はp210 BCR-ABL1遺伝子を発現した造血幹細胞のクローン性疾患であるにもかかわらず、末梢血のT細胞あるいはB細胞にはp210 BCR-ABL1は検出されない。その病態を解明するため、p210 BCR-ABL1の造血幹細胞からリンパ球系細胞への分化に対する作用を検討した。ヒト臍帯血CD34^+細胞をサイトカインthrombopoietin、c-kit ligand、FLT3 ligandとともにヒト骨髄由来ストローマ細胞上で培養した。p210 BCR-ABL1が導入されていないCD34^+細胞からはCD19^+ B細胞とCD7^+ T細胞が産生されたが、p210 BCR-ABL1が導入されたCD34^+細胞の培養ではCD19^+細胞とCD7^+細胞は検出されなかった。CMLではリンパ球系細胞が疾患に巻き込まれていないのは、p210 BCR-ABL1による造血幹細胞のリンパ球への分化能の抑制が関わっていることが示唆された。B細胞性急性リンパ性白血病(B-ALL)においては、p210 BCR-ABL1あるいはp190 BCR-ABL1が認められるが、いずれの遺伝子の検出例においても多くはIkaros遺伝子の異常(dominant negative isoform;IK6)を伴っている。そこで、p210 BCR-ABL1あるいはp190 BCR-ABL1とIK6のB-ALL発症における協調作用をヒト臍帯血CD34^+細胞にこれらの遺伝子を導入することで検討した。p210 BCR-ABL1あるいはp190 BCR-ABL1とIK6を導入されたCD34^+細胞はそれぞれの遺伝子を単独で導入したCD34^+細胞に比べ、増殖能が亢進していたが、B-ALL様の細胞は見られなかった。BCR-ABL1^+ B-ALLの発症には他の付加的な因子が必要であると思われる。

Research Products

• [Journal Article] CD5-positive diffuse large B-cell lymphoma : a retrospective study in 337 patients treated by chemotherapy with or without rituximab (2011)
  • Author(s): Miyazaki K, et al
  • Journal Title: Ann Oncol Volume: 22 Pages: 1601-1607
  • DOI: 10.1093/annonc/mdq627
  • Peer Reviewed
• [Journal Article] Clonal evolution of adult T-cell leukemia/lymphoma takes place in lymph node (2011)
  • Author(s): Umono A, et al
  • Journal Title: Blood Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Elevated Von Willebrand factor propeptide for the diagnosis of thrombotic microangiopathy and for predicting a poor outcome (2011)
  • Author(s): Ito-Habe N, et al
  • Journal Title: Int J Hematol Volume: 93 Pages: 47-52
  • Peer Reviewed
• [Journal Article] Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation (2011)
  • Author(s): Takemitsu T, et al
  • Journal Title: Thromb Haemost Volume: 105 Pages: 40-44
  • Peer Reviewed
• [Journal Article] Correlation between imatinib pharmacokinetics and clinical response in Japanese patients with chronic-phase chronic myeloid leukemia (2010)
  • Author(s): Takahashi N, et al
  • Journal Title: Clin Pharmacol Ther Volume: 88 Pages: 809-813
  • Peer Reviewed
• [Journal Article] A potential activity of valproic acid in the stimulation of interleukin-3-mediated megakaryopoiesis and erythropoiesis (2010)
  • Author(s): Liu B, et al
  • Journal Title: Exp Hematol Volume: 38 Pages: 685-695
  • Peer Reviewed
• [Journal Article] Drug interaction between itraconazole and bortezomib : exacerbation of peripheral neuropathy and thrombocytopenia induced by bortezomib (2010)
  • Author(s): Iwamoto T, et al
  • Journal Title: Pharmacotherapy Volume: 30 Pages: 661-665
  • Peer Reviewed
• [Journal Article] Diagnostic value of PCR analysis of bacteria and fungi from blood in empiric-therapy-resistant febrile neutropenia (2010)
  • Author(s): Nakamura A, et al
  • Journal Title: J Clin Microbiol Volume: 48 Pages: 2030-2036
  • Peer Reviewed
• [Journal Article] High-intensity signals in the basal ganglia from gadolinium-enhanced T1-weighted MRI as an early change in toxoplasma encephalitis in an AIDS patient (2010)
  • Author(s): Suzuki K, et al
  • Journal Title: J Infect Chemother Volume: 16 Pages: 135-138
  • Peer Reviewed
• [Presentation] Gene expression profiling of diffuse large B-cell lymphomas supervised by CD5 expression (2010)
  • Author(s): Miyazaki K, et al
  • Organizer: 52^<ND> American Society of Hematology Annual Meeting
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2010-12-06
• [Presentation] Valproic acid results in maintenance but not expansion of transplantable hematopoietic stem cells from human umbilical cord blood (2010)
  • Author(s): Araki H, et al
  • Organizer: 52^<ND> American Society of Hematology Annual Meeting
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2010-12-06
• [Presentation] Important role for flt3 ligand in the generation of early B and T cell precursors from human primitive hematopoietic progenitors, revealed by telomerized human stromal cells (2010)
  • Author(s): Liu B, et al
  • Organizer: 52^<ND> American Society of Hematology Annual Meeting
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2010-12-05
• [Presentation] Array comparative genomic hybridization revealed polyclonality in acute type adult T-cell leukemia/lymphoma and PTCL NOS (2010)
  • Author(s): Umino A, et al
  • Organizer: 52^<ND> American Society of Hematology Annual Meeting
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2010-12-05
• [Presentation] TMA患者におけるVWF propeptide値の検討 (2010)
  • Author(s): 波部尚美、和田英夫、登勉、片山直之
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-26
• [Presentation] Prospective study on evaluation of DIC diagnostic criteria by three different diagnostic criteria (2010)
  • Author(s): Wada H, Matsumoto T, Ohishi K, Itoh-Habe N, Katayama N, Nobori T
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-26
• [Presentation] Ikaros isoform 6 enhances proliferative effect by BCR-ABL1 in human CD34+ hematopoietic cells (2010)
  • Author(s): Suzuki K, Ono R, Ohishi K, Kataoka I, Masuya M, Hamadan H, Kitamura T, Katayama N, Nosaka T
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-26
• [Presentation] Diagnostic value of granulocytosis for prediction of JAK2 mutation in polycythemic patients (2010)
  • Author(s): Ohishi K, Matsuo Y, Abe Y, Tamaki S, Usui E, Matsumoto T, Fujieda A, Miyazaki K, Kobayashi K, Monma F, Masuya M, Tamaru S, Nishikawa M, Nishioka J, Nobori T, Katayama N
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-26
• [Presentation] BM CD34+ cells expanded on HUBEC reconstitutes lethally irradiated baboons in a variable manner (2010)
  • Author(s): Araki H, Mahmud N, Katayama N
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-25
• [Presentation] A retrospective study of 31 patients with NK/T-cell lymphoma : Mie University Hospital experience (2010)
  • Author(s): Miyazaki K, Yamaguchi M, Ii N, Nomoto Y, Yuta A, Imai H, Masahiro Masuya M, Nakase K, Katayama N
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-25
• [Presentation] CD5陽性びまん性大細胞型B細胞リンパ腫の新規治療開発に向けた免疫組織化学による各種抗原発現の検討 (2010)
  • Author(s): 江間菜々恵、山口素子、宮崎香奈、片山直之
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-25
• [Presentation] 遺伝子組み換えトロンボモジュリン投与による各種凝血学的マーカーの変動 (2010)
  • Author(s): 松本剛史、和田英夫、鈴木彦次、岡宏次、渡邉泰行、上村泰弘、豊田秀実、塚田哲也、門間文彦、藤枝敦史、大石晃嗣、桝屋正浩、片山直之
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-25
• [Presentation] T-prolymphocytic leukemia : a case report (2010)
  • Author(s): Tamaru S, et al
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-25
• [Presentation] 各種化学療法に抵抗性を示したALK陽性未分化大細胞型リンパ腫の一例 (2010)
  • Author(s): 南博仁, 他
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-25
• [Presentation] PCR for detection of pathogenic bacteria in early phase of hematopoietic cell transplantation (2010)
  • Author(s): Fujieda A, Nakamura A, Ohishi K, Miyazaki K, Monma F, Matsumoto T, Yamaguchi M, Masuya M, Nakase K, Wada H, Nobori T, Katayama N
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] Diagnostic utility of PCR analysis of bacteria and fungus from blood in febrile neutropenia (2010)
  • Author(s): Ohishi K, Nakamura A, Sugimoto Y, Sugawara Y, Fujieda A, Monma F, Masuya M, Nakase K, Matsushima K, Wada H, Nobori T, Katayama N
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] Hematopoietic origin of pancreatic stellate cells (2010)
  • Author(s): Ino K, Masuya M, Miyata E, Ohishi K, Katayama N
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] Crucial role of flt3 ligand in human early B/T lymphopoiesis revealed by telomerized stromal cells (2010)
  • Author(s): Liu B, Ohishi K, Suzuki K, Masuya M, Hamada H, Nishikawa H, Shiku H, Katayama N
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] A fatal complication of Clostridium perfringens septicemia in a patient with acute myeloid leukemia (2010)
  • Author(s): Monma F, et al
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Book] 今日の治療指針2011 (2011)
  • Author(s): 片山直之
  • Total Pages: 1978
  • Publisher: 医学書院
• [Book] 血液疾患最新の治療2011-2013 (2010)
  • Author(s): 片山直之
  • Total Pages: 408
  • Publisher: 南江堂