ゲノムワイドなメチル化解析による若年性骨髄単球性白血病のリスク分類の開発

2011 Fiscal Year Annual Research Report

• Project/Area Number: 22790975
• Research Institution: Nagoya University
• Principal Investigator: 村松 秀城 名古屋大学, 医学部附属病院, 助教 (00572570)
• Keywords: 若年性骨髄単球性白血病 / メチル化解析 / エピジェネティック

Research Abstract

若年性骨髄単球性白血病(Juvenile myelomonocytic leukemia; JMML)はまれな小児特有の白血病である。一般に化学療法のみでは治癒が望めず、全例を対象として同種造血幹細胞移植による治療が行われているが、なお長期生存率は40-50%と不良であり、新規治療の開発が求められている。一方、無治療で長期間生存が得られている患者群の存在も報告されており、適切なリスク分類に基づく治療層別化が必要である。本研究の目的は、JMMLを対象にメチル化アレイによるゲノムワイドなエピジェネティック情報解析を行い、JMMLの病態生理における遺伝子メチル化の関与の解明および新規リスク分類の開発を目指すことにある。
平成22年度中に、我々はJMML49例のgenomic DNAを抽出し、バイサルファイト処理およびwhole genome amplificationを行い、パイロシークエンス法を用いて10種類以上の遺伝子プロモーター領域のメチル化の確認を行った。平成23年度には、各遺伝子のメチル化状態と生命予後等の臨床情報との関連について、統計学的手法を用いて解析した。正常検体と比較して、CDKN2A、H19、CALCA、IGF2、BMP4の各遺伝子プロモーター領域の有意なメチル化亢進が確認された。海外からの報告と異なり、本研究による日本人JMML検体での検討では、遺伝子メチル化と全生存率との有意な相関は認められなかった。本研究結果から、JMML症例において遺伝子メチル化は亢進しているものの、遺伝子メチル化を組み込んだ予後予測リスク分類への適用は困難であることが判明した。

Research Products

• [Journal Article] Molecular lesions in childhood and adult acute megakaryoblastic leukaemia (2012)
  • Author(s): Hama A, Muramatsu H, Makishima H, Sugimoto Y, Szpurka H, Jasek M, O' Keefe C, Takahashi Y, Sakaguchi H, Doisaki S, Shimada A, Watanabe N, Kato K, Kiyoi H, Naoe T, Kojima S, Maciejewski JP
  • Journal Title: British journal of haematology Volume: 156 Pages: 316-325
  • Peer Reviewed
• [Journal Article] Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia : novel pathogenetic lesions (2012)
  • Author(s): Muramatsu H, Makishima H, Maciejewski JP
  • Journal Title: Seminars in oncology Volume: 39 Pages: 67-73
  • Peer Reviewed
• [Journal Article] Incidence, clinical features, and risk factors of idiopathic pneumonia syndrome followins hematopoietic stem cell transplantation in children (2012)
  • Author(s): Sakaguchi H, et al
  • Journal Title: Pediatric blood & cancer Volume: 58 Pages: 780-784
  • DOI: 10.1002/pbc.23298.
  • Peer Reviewed
• [Journal Article] Excellent outcomes of children with CML treated with imatinib mesylate compared to that in pre-imatinib era (2011)
  • Author(s): Muramatsu H, Takahashi Y, Sakaguchi H, Shimada A, Nishio N, Hama A, Doisaki S, Yagasaki H, Matsumoto K, Kato K, Kojima S
  • Journal Title: International journal of hematology Volume: 93 Pages: 186-191
  • Peer Reviewed
• [Journal Article] CD20-negative Epstein-Barr virus-associated post-transplant lymphoproliferative disease refractory to rituximab in a patient with severe aplastic anemia (2011)
  • Author(s): Muramatsu H, Takahashi Y, himoyama Y, Doisaki S, Nishio N, Ito Y, Hama A, Shimada A, Yagasaki H, Ito M, Kojima S
  • Journal Title: International journal of hematology Volume: 93 Pages: 779-781
  • Peer Reviewed
• [Journal Article] Total body irradiation and melphalan as a conditioning regimen for children with hematological malignancies undergoing transplantation with stem cells from HLA-identical related donors (2011)
  • Author(s): Watanabe N, Takahashi Y, Matsumoto K, Horikoshi Y, Hama A, Muramatsu H, Yoshida N, Yagasaki H, Kudo K, Horibe K, Kato K, Kojima S
  • Journal Title: Pediatr Transplant Volume: 15 Pages: 642-649
  • Peer Reviewed
• [Journal Article] Prognostic factors for outcomes of pediatric patients with refractory or relapsed acute leukemia undergoing allogeneic progenitor cell transplantation (2011)
  • Author(s): Watanabe N, Takahashi Y, Matsumoto K, Hama A, Muramatsu H, Doisaki S, Horibe K, Kato K, Kojima S
  • Journal Title: Biol Blood Marrow Transplant Volume: 17 Pages: 516-523
  • Peer Reviewed
• [Journal Article] Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation (2011)
  • Author(s): Takagi M, Shinoda K, Piao J, Mitsuiki N, Matsuda K, Muramatsu H, Doisaki S, Nagasawa M, Morio T, Kasahara Y, Koike K, Kojima S, Takao A, Mizutani S
  • Journal Title: Blood Volume: 117 Pages: 2887-2890
  • Peer Reviewed
• [Journal Article] Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia (2011)
  • Author(s): Shima H, Tokuyama M, Tanizawa A, Tono C, Hamamoto K, Muramatsu H, Watanabe A, Hotta N, Ito M, Kurosawa H, Kato K, Tsurusawa M, Horibe K, Shimada H
  • Journal Title: J Pediatr Volume: 159 Pages: 676-681
  • Peer Reviewed
• [Journal Article] Aberrant phosphorylation of STAT5 by granulocyte-macrophage colony-stimulating factor in infant cytomegalovirus infection mimicking juvenile myelomonocytic leukemia (2011)
  • Author(s): Nishio N, Takahashi Y, Tanaka M, Xu Y, Yoshida N, Sakaguchi H, Doisaki S, Hama A, Muramatsu H, Shimada A, Kojima S
  • Journal Title: Leukemia research Volume: 35 Pages: 1261-1264
  • Peer Reviewed
• [Journal Article] Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita (2011)
  • Author(s): Nishio N, Takahashi Y, Ohashi H, Doisaki S, Muramatsu H, Hama A, Shimada A, Yagasaki H, Kojima S
  • Journal Title: Pediatr Transplant Volume: 15 Pages: 161-166
  • Peer Reviewed
• [Journal Article] Relapse of aplastic anemia in children after immunosuppressive therapy : a report from the Japan Childhood Aplastic Anemia Study Group (2011)
  • Author(s): Kamio T, Ito E, Ohara A, Kosaka Y, Tsuchida M, Yagasaki H, Mugishima H, Yabe H, Morimoto A, Ohga S, Muramatsu H, Hama A, Kaneko T, Nagasawa M, Kikuta A, Osugi Y, Bessho F, Nakahata T, Tsukimoto I, Kojima S
  • Journal Title: Haematologica Volume: 96 Pages: 814-819
  • Peer Reviewed
• [Journal Article] Analysis of mutations and recombination activity in RAG-deficient patients (2011)
  • Author(s): Asai E, Wada T, Sakakibara Y, Toga A, Toma T, Shimizu T, Nampoothiri S, Imai K, Nonoyama S, Morio T, Muramatsu H, Kamachi Y, Ohara O, Yachie A
  • Journal Title: Clin Immunol Volume: 138 Pages: 172-177
  • Peer Reviewed
• [Journal Article] Mutations profile of polycythemia vera and essential thrombocythemia among Japanese children (2011)
  • Author(s): Ismael O, et al
  • Journal Title: Pediatric blood & cancer Volume: (In press)
  • DOI: 10.1002/pbc.23409
  • Peer Reviewed
• [Journal Article] Autoimmune-like hepatitis following unrelated BMT successfully treated with rituximab
  • Author(s): Narita A, et al
  • Journal Title: Bone marrow transplantation Volume: 2011(In press)
  • DOI: 10.1038/bmt.2011.124
  • Peer Reviewed
• [Presentation] 若年性骨髄単球性白血病におけるDNAメチル化の臨床的意義 (2011)
  • Author(s): 坂口大俊, 他
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] NRAS体細胞モザイク変異(G12D)により若年性骨髄単球性白血病を発症した一例 (2011)
  • Author(s): 土居崎小夜子, 他
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15