DNA mismatch repair deficiency in paediatric haematological malignancies: research and application for chemotherapeutic strategies

• Project/Area Number: 22591173
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Hospital Organization, Kyushu Cancer Center
• Principal Investigator: OKAMURA Jun 独立行政法人国立病院機構(九州がんセンター臨床研究センター), その他の部局等 (40360854)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 小児腫瘍学 / 血液腫瘍 / 化学療法 / 薬剤反応性 / DNA 修復 / 癌 / DNA修復

Research Abstract

This study aimed to elucidate the reality of DNA mismatch repair (MMR) deficiency in the paediatric haematological malignancies, particularly acute lymphocytic leukaemia (ALL) and non-Hodgkin lymphoma, and, consequently, the relationship between the MMR status and the chemosensitivity of tumours against methotrexate (MTX) and 6-mercatutopurine (6-MP) in this category of human malignancies. In a panel of 30 ALL patients, we analysed microsatellite instability (MSI) in the tumour DNA and found a few MSI-positive tumours. However, the detailed examination of the clinical backgrounds of the patients revealed that the observed microsatellite alterations reflected the haematopoietic stem cell transplantation that they underwent, which suggests that MSI analysis is not applicable to some cases of haematological malignancies. Multi-angle analysis is needed in this subject.

Research Products

• [Journal Article] Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia : a retrospective cohort study (2012)
  • Author(s): Junya Kanda
  • Journal Title: Blood Volume: 119 Issue: 9 Pages: 2141-2148
  • DOI: 10.1182/blood-2011-07-368233
  • Peer Reviewed
• [Journal Article] Japanese Paediatric Myelodysplastic Syndrome (MDS) Study Group: Outcome of children with Refractory Anaemia with excess of blast (RAEB) and RAEB in Transformation (RAEB-T) in the Japanese MDS99 study (2012)
  • Author(s): Kikuchi A, Hasegawa D, Ohtsuka Y, Hamamoto K, Kojima S, Okamura J, Nakahata T, Manabe A
  • Journal Title: Br J Haematol Volume: 158 Pages: 657-661
• [Journal Article] Successful treatment with plasma exchange for disseminated cidofovir - resistant adenovirus disease in a pediatric SCT recipient (2012)
  • Author(s): Nishikawa T, Nakashima K, Fukano R, Okamura J, Inagaki J
  • Journal Title: Bone Marrow Transplant Volume: 47 Issue: 8 Pages: 1138-1139
  • DOI: 10.1038/bmt.2011.227
  • Peer Reviewed
• [Journal Article] The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT:long-term outcomes (2012)
  • Author(s): Nishikawa T, Inagaki J, Nagatoshi Y, Fukano R, Nakashima K, Ito N, Sawa D, Kawano Y, Okamura J
  • Journal Title: Pediatr Transplant Volume: 16 Issue: 7 Pages: 722-728
  • DOI: 10.1111/j.1399-3046.2012.01737.x
  • Peer Reviewed
• [Journal Article] Outcome of children with Refractory Anaemia with Excess of Blast (RAEB) and RAEB in Transformation (RAEB-T) in the Japanese MDS99 study. (2012)
  • Author(s): Kikuchi A.
  • Journal Title: Brit. J. Haematol. Volume: 158 Issue: 5 Pages: 657-661
  • DOI: 10.1111/j.1365-2141.2012.09210.x
  • Peer Reviewed
• [Journal Article] Impact of graft-versus-host disease on outcomes after allogeneic Hematopoietic cell transplantation for adult T-cell leukemia : a retrospec tive cohort study (2012)
  • Author(s): Kanda J, et al
  • Journal Title: Blood Volume: 119 Pages: 2141-2148
  • Peer Reviewed
• [Journal Article] TBI and melphalan followed by allogeneic hematopoietic SCT in children with advanced hematological malignancies (2011)
  • Author(s): Inagaki J, Nagatoshi Y, Sakiyama M, Nomura Y, Teranishi H, Sasaki T, Okamura J
  • Journal Title: Bone Marrow Transplant Volume: 46 Issue: 8 Pages: 1057-1062
  • DOI: 10.1038/bmt.2010.253
• [Journal Article] Social outcomes and quality of life of childhood cancer survivors in Japan: a cross-sectional study on marriage, education, employment and health-related QOL (SF-36) (2011)
  • Author(s): Ishida Y, Honda M, Kamibeppu K, Ozono S, Okamura J, Asami K, Maeda N, Sakamoto N, Inada H, Iwai T, Kakee N, Horibe K.
  • Journal Title: Int J Hematol Volume: 93 Issue: 5 Pages: 635-644
  • DOI: 10.1007/s12185-011-0843-6
  • NAID: 10029535150
• [Journal Article] TBI and melphalan followed by allogeneic hematopoietic SCT in children with advanced hematological malignancies (2011)
  • Author(s): Inagaki J, et al
  • Journal Title: Bone Marrow Transp Volume: 46 Pages: 1057-1062
  • Peer Reviewed
• [Journal Article] Social outcomes and quality of life of childhood cancer survivors in Japan : a cross-sectional study on marriage, education, employment and health-related QOL (SF-36) (2011)
  • Author(s): Ishida Y, et al
  • Journal Title: Int J Hematol Volume: 93 Pages: 633-644
  • Peer Reviewed
• [Journal Article] Long-term outcomes after hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma: results of prospective trials (2010)
  • Author(s): Choi I, Tanosaki R, Uike N, Utsunomiya A, Tomonaga M, Harada M, Yamanaka T, Kannagi M, Okamura J
  • Journal Title: Bone Marrow Transplant Volume: 46 Issue: 1 Pages: 116-118
  • DOI: 10.1038/bmt.2010.92
• [Journal Article] Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study (2010)
  • Author(s): Hishizawa M, Kanda J, Utsunomiya A, Taniguchi S, Eto T, Moriuchi Y, Tanosaki R, Kawano F, Miyazaki Y, Masuda M, Nagafuji K, Hara M, Takanashi M, Kai S, Atsuta Y, Suzuki R, Kawase T, Matsuo K, Nagamura-Inoue T, Kato S, Sakamaki H, Morishima Y, Okamura J, Ichinohe T, Uchiyama T
  • Journal Title: Blood Volume: 116 Issue: 8 Pages: 1369-1376
  • DOI: 10.1182/blood-2009-10-247510
• [Journal Article] Late effects and quality of life of childhood cancer survivors: Part 2. Impact of radiotherapy (2010)
  • Author(s): Ishida Y, Sakamoto N, Kamibeppu K, Kakee N, Iwai T, Ozono S, Maeda N, Okamura J, Asami K, Inada H, Honda M, Horibe K
  • Journal Title: Int J Hematol Volume: 92 Issue: 1 Pages: 95-104
  • DOI: 10.1007/s12185-010-0611-z
  • NAID: 10026512130
• [Journal Article] Long-term outcomes after hematopoietic stem cell transplantation for adult T-cell leukemia/lymphoma : results of prospective trials. (2010)
  • Author(s): Choi I, et al.
  • Journal Title: Bone Marrow Transplant Volume: 46 Pages: 116-118
  • Peer Reviewed
• [Journal Article] Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia : a nationwide retrospective study. (2010)
  • Author(s): Hishizawa M, et al.
  • Journal Title: Blood Volume: 116 Pages: 1369-1376
  • Peer Reviewed
• [Journal Article] Late effects and quality of life of childhood cancer survivors : Part 2. Impact of radiotherapy. (2010)
  • Author(s): Ishida Y, et al.
  • Journal Title: Int J Hematol Volume: 92 Pages: 95-104
  • Peer Reviewed
• [Presentation] Identification of a novel HLA-DR1-retricted dominant epitope recognized by HTLV-1 Tax-specific CD4+ T-cells augmenting HTLV-1-specific CTL expansion in ATL patients after allogeneic HSCT (2013)
  • Author(s): Hasegawa A, Tamai Y, Takamori A, Sasada A, Tanosaki R, Choi I, Utsunomiya A, Maeda Y, Yamano Y, Eto T, Koh K, Nakamae H, Suehiro Y, Kato K, Takemoto S, Okamura J, Uike N, Kannagi M
  • Organizer: The 9th Joint Conference of the American Association forCancer Research and the Japanese Cancer Association
  • Place of Presentation: Maui
  • Year and Date: 2013-02-21
• [Presentation] dentificant of a novel HLA-DR1-retricted dominant epitope recognized by HTLV-1 Tax-specific CD4+ T-cells augmenting HTLV-1-specific CTL expansion in ATL patients after allogeneic HSCT. (2013)
  • Author(s): Hasegawa A
  • Organizer: The 9th Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association
  • Place of Presentation: 米国ハワイ州
• [Presentation] ステロイド抵抗性aGVHDに対する低用量メソトレキセート (2013)
  • Author(s): 稲垣二郎
  • Organizer: 第35回日本造血細胞移植学会総会
  • Place of Presentation: 金沢
• [Presentation] 骨髄非破壊的前処置による非血縁者間臍帯血移植を施行した重症再生不良性貧血の女児例 (2013)
  • Author(s): 西村美穂
  • Organizer: 第35回日本造血細胞移植学会総会
  • Place of Presentation: 金沢
• [Presentation] 小児ALLの同種造血幹細胞移植におけるCNS再発予防を目的とした移植前頭蓋照射の有効性 (2013)
  • Author(s): 深野玲司
  • Organizer: 第35回日本造血細胞移植学会総会
  • Place of Presentation: 金沢
• [Presentation] Identification of a novel HLA-DR1-restricted epitope that is recognized by Tax-specific CD4+ T cells with the potential to enhance Tax-specific CD8+ responses in ATL patients after allo-HSCT (2012)
  • Author(s): Tamai Y, Hasegawa A, Takamori A, Sasada A, Tanosaki R, Choi I, Utsunomiya A, Etoh T, Koh H, Suehiro Y, Okamura J, Uike N, Kannagi M
  • Organizer: 第71回日 本癌学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-19
• [Presentation] Clinical trial of unrelated bone marrow transplantation with reduced intensity conditioning for elderly ATL patient (2012)
  • Author(s): Choi I, Eto T, Tanosaki R, Utsunomiya A, Fukushima T, Teshima T, Suehiro Y, Yamanaka T, Okamura J, Uike N
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-19
• [Presentation] Identification of a novel HLA-DR1-restricted epitope that is recognized by Tax-specific CD4+ T cells with the potential to enhance Tax-specific CD8+ responses in ATL patients after allo-HSCT. (2012)
  • Author(s): Tamai Y
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] 成人T細胞白血病/リンパ腫に対する骨髄非破壊的前処置を用いた非血縁骨髄移植の多施設共同臨床試験 (2012)
  • Author(s): 崔日承
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] Stem cell transplantation for acute leukemia with t(10;11)(p12;q14) (2012)
  • Author(s): Nishikawa T
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Necrotizing soft tissue infections accompanied by graft-versus-host disease after donor lymphocyte infusion for acute lymphoblastic leukemia. (2012)
  • Author(s): Ito N
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Successful treatment with dasatinib and 2nd allo-SCT for very late relapse of Ph-ALL. (2012)
  • Author(s): Honda E
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Combined analysis of treatments for pediatric ALL in KYCCSG protocols,ALL-96 and ALL-02. (2012)
  • Author(s): Okamoto Y
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Long-term follow-up for children with SAA and RCC received 3 Gy TBI containing conditioning regimen. (2012)
  • Author(s): Inagaki J
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] AMLの治療中に、血液のPCRにてPseudallescheria boydiiとGeotrichum candidumが検出された7歳男児例 (2012)
  • Author(s): 中島健太郎
  • Organizer: 第115回日本小児科学会学術集会
  • Place of Presentation: 福岡
• [Presentation] A prospective Feasibility trial of unrelated bone marrow transplantation with reduced intensity conditioning regimen for elderly patients with adult T-cell leukemia/lymphoma (ATL) (2011)
  • Author(s): Eto T, Choi I, Tanosaki R, Takatsuka Y, Utsunomiya A, Takemoto S, Taguchi J, Fukushima T, Kato K, Teshima T, Suehiro Y, Yamanaka T, Okamura J, Uike N
  • Organizer: 53th American Society of Hematology Annual meeting and Exposition
  • Place of Presentation: San Diego
  • Year and Date: 2011-12-10
• [Presentation] A prospective Feasibility trial of unrelated bone marrow transplantation with reduced intensity conditioning regimen for elderly patients with a dult T-cell leukemia/lymphoma (ATL) (2011)
  • Author(s): Eto T, et al
  • Organizer: 53th American society of Hematology annual meeting and exposition
  • Place of Presentation: San Diego
  • Year and Date: 2011-12-10
• [Presentation] Functional impairment of Tax-specific but not CMV-specific CTLs in a minor population of asymptomatic HTLV-I-carriers (2011)
  • Author(s): Hasegawa A, Takamori A, Utsunomiya A, Maeda Y, Yamano Y, Shimizu Y, Tamai Y, Sasada A, Zeng N, Choi I, Uike N, Okamura J, Watanabe T, Masuda T, Kannagi
  • Organizer: 15th International Conference on Human Retrovirology
  • Place of Presentation: Leuven
  • Year and Date: 2011-06-05
• [Presentation] Can allo-SCT with RIC cure ATLL? (2011)
  • Author(s): Uike N, Tanosaki R, Utsunomiya A, Choi I, Okamura J
  • Organizer: Long-term survivors with excellent PS and with heterogenous HTLV-1 proviral load level
  • Place of Presentation: Leuven
  • Year and Date: 2011-06-05
• [Presentation] Can allo-SCT with RIC cure ATLL? : Long-term survivors with excellent PS and with heterogenous HTLV-1 proviral load level (2011)
  • Author(s): Uike N, et al
  • Organizer: 15th International Conference on Human Retrovirology
  • Place of Presentation: Leuven
  • Year and Date: 2011-06-05
• [Presentation] Antiviral effect of allo-SCT with RIC for ATLL: Short and long-term kinetics of HTLV-1proviral load (2010)
  • Author(s): Choi I, Tanosaki R, Uike N, Utsunomiya A, Okamura J
  • Organizer: The 1st International Society of Cell Therapy (ISCT) Asia-Pacific Regional Meeting
  • Place of Presentation: 宮崎
  • Year and Date: 2010-10-19
• [Presentation] Antiviral effect of allo-SCT with RIC for ATLL : Short and long-term kinetics of HTLV-1proviral load. (2010)
  • Author(s): Choi I, et al.
  • Organizer: The 1st International Society of Cell Therapy (ISCT) Asia-Pacific Regional Meeting
  • Place of Presentation: Miyazaki
  • Year and Date: 2010-10-19