Analysis of pathogenesis of refractory childhood myelodysplastic syndrome using disease-specific iPS cells

• Project/Area Number: 21390308
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Shinshu University
• Principal Investigator: KOIKE Kenichi 信州大学, 医学部, 教授 (40143979)
• Co-Investigator(Kenkyū-buntansha): SHIOHARA Masaaki 信州大学, 医学部, 准教授 (00293514) ; 坂下 一夫 信州大学, 医学部附属病院, 助教 (10345746)
• Co-Investigator(Renkei-kenkyūsha): SAKASHITA Kazuo 信州大学, 医学部・附属病院, 助教 (10345746)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2011: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2010: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2009: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 小児血液学 / 骨髄異形成症候群 / iPS細胞 / 白血病性幹細胞 / JMML / 造血幹細胞

Research Abstract

The cultured CD34-positive cells of juvenile myelomonocytic leukemia(JMML) patient were transfected the Yamanaka 4 genes, and cultured on mouse embryonic fibroblasts. Two-3 weeks later, many cell clusters with the RAS mutation were formed and negative for CD34. These cells were compatible with induced pluripotent(iPS) stem cells. We succeeded the establishment of iPS cells with myeloid differentiation potencial from the cultured JMML CD34-positive cells. We are going to elucidate pathogenesis of JMML and properties of the leukemic stem cells.

Research Products

• [Journal Article] Long-term haematological improvement after non-intensive or no chemotherapy in juvenile myelomonocytic leukaemia and poor correlation with adult myelodysplasia spliceosome-related mutations (2012)
  • Author(s): Matsuda K, Yoshida N, Miura S, Nakazawa Y, Sakashita K, Hyakuna N, Saito M, Kato F, Ogawa A, Watanabe A, Sotomatsu M, Kobayashi C, Ito T, Ishida F, Manabe A, Kojima S, Koike K
  • Journal Title: Br J Haematol Volume: 157 Pages: 647-50
  • Peer Reviewed
• [Journal Article] Genetic evaluation of childhood acute lymphoblastic leukemia in Iraq using FTA cards (2012)
  • Author(s): Al-Kzayer LF, Sakashita K, Matsuda K, Al-Hadad SA, Al-Jadiry MF, Abed WM, Abdulkadhim JM, Al-Shujairi TA, Hasan JG, Al-Abdullah HM, Al-Ani MH, Saber PA, Inoshita T, Kamata M, Koike K
  • Journal Title: Pediatr Blood Cancer Volume: 59 Issue: 3 Pages: 461-7
  • DOI: 10.1002/pbc.24055
  • Peer Reviewed
• [Journal Article] Critical illness polyneuropathy and myopathy caused by bacillus cereus sepsis in acute lymphoblastic leukemia (2012)
  • Author(s): Hirabayashi K, Shiohara M, Suzuki T, Saito S, Tanaka M, Yanagisawa R, Tsuruta G, Fukuyama T, Hidaka Y, Nakazawa Y, Shimizu T, Sakashita K, Koike K
  • Journal Title: J Pediatr Hematol Oncol Volume: 34 Pages: 110-3
  • Peer Reviewed
• [Journal Article] Genetic analysis of TP53 in childhood myelodysplastic syndrome and juvenile myelomonocytic leukemia (2011)
  • Author(s): Saito S, Matsuda K, Taira C, Sano K, Tanaka-Yanagisawa M, Yanagisawa R, Nakazawa Y, Sakashita K, Shiohara M, Koike K
  • Journal Title: Leuk Res. Volume: 35 Pages: 1578-84
  • NAID: 120007108235
  • Peer Reviewed
• [Journal Article] Retrospective analysis of risk factors for development of liver dysfunction in transient leukemia of Down syndrome (2011)
  • Author(s): Hirabayashi K, Shiohara M, Takahashi D, Saito S, Tanaka M, Yanagisawa R, Sakashita K, Nakamura T, Ishii E, Koike K
  • Journal Title: Leuk Lymphoma Volume: 52 Pages: 1523-7
  • Peer Reviewed
• [Journal Article] Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation (2011)
  • Author(s): Takagi M, Shinoda K, Piao J, Mitsuiki N, Takagi M, Matsuda K, Muramatsu H, Doisaki S, Nagasawa M, Morio T, Kasahara Y, Koike K, Kojima S, Takao A, Mizutani
  • Journal Title: Blood Volume: 117 Pages: 2887-90
  • Peer Reviewed
• [Journal Article] Engraftment syndrome, but not acute graft-versus-host disease, younger age, CYP3A5 or MDR1 polymorphisms, increases tacrolimus clearance in pediatric hematopoietic stem cell transplantation (2011)
  • Author(s): Yanagisawa R, Katsuyama Y, Shigemura T, Saito S, Tanaka M, Nakazawa Y, Sakashita K, Shiohara M, Koike K
  • Journal Title: Bone Marrow Transplantation Volume: 46 Pages: 90-97
  • Peer Reviewed
• [Journal Article] Disappearance of minimal residual disease after the early withdrawal of immunosuppressants in a patient with juvenile myelomonocytic leukemia (2011)
  • Author(s): Yanagisawa R, Matsuda K, Sakashita K, Nakazawa Y, Tanaka M, Saito S, Yoshikawa K, Kamijo T, Shiohara M, Koike K
  • Journal Title: Pediatr Blood Cancer Volume: 56 Pages: 501-2
  • Peer Reviewed
• [Journal Article] Genetic analysis of TP53 in childhood myelodysplastic syndrome and juvenile myelomonocytic leukemia (2011)
  • Author(s): Saito S, Matsuda K, Taira C, Sano K, Tanaka-Yanagisawa M, Yanagisawa R, Nakazawa Y, Sakashita K, Shiohara M, Koike K
  • Journal Title: Leuk Res Volume: 35 Pages: 1578-84
  • NAID: 120007108235
  • Peer Reviewed
• [Journal Article] Disappearance of minimal residual disease after the early withdrawal of immnunosuppressants in a patient with juvenile myelomonocytic leukemia (2011)
  • Author(s): Yanagisawa R, Matsuda K, Sakashita K, Nakazawa Y, Tanaka M, Saito S, Yoshikawa K, Kamijo T, Shiohara M, Koike K
  • Journal Title: Pediatr Blood Cancer Volume: 56 Issue: 3 Pages: 166-71
  • DOI: 10.1002/pbc.22849
  • Peer Reviewed
• [Journal Article] Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. (2011)
  • Author(s): Takagi M, Matsuda K, Koike K, et, al.
  • Journal Title: Blood Volume: 117 Pages: 2887-90
  • Peer Reviewed
• [Journal Article] Engraftment syndrome, but not acute graft-versus-host disease, younger age, CYP3A5 or MDR1 polymorphisms, increases tacrolimus clearance in pediatric hematopoietic stem cell transplantation. (2011)
  • Author(s): Yanagisawa R, Katsuyama Y, Shigemura T, Saito S, Koike K, et, al.
  • Journal Title: Bone Marrow Transplantation Volume: 2011 Pages: 90-7
  • Peer Reviewed
• [Journal Article] Disappearance of minimal residual disease after the early withdrawal of immunosuppressants in a patient with juvenile myelomonocytic leukemia. (2011)
  • Author(s): Yanagisawa R Matsuda K, Koike K, et, al.
  • Journal Title: Pediatr Blood Cancer Volume: 56 Pages: 501-2
  • Peer Reviewed
• [Journal Article] HDM2 impairs Noxa transcription and affects apoptotic cell death in a p53/p73-dependent manner in neuroblastoma. (2011)
  • Author(s): Shi Y, Koike K, Kamijo T, et, al.
  • Journal Title: Eur J Cancer Volume: 46 Pages: 2324-34
  • Peer Reviewed
• [Journal Article] Increased pretransplant QT dispersion as a risk factor for the development of cardiac complications during and after preparative conditioning for pediatric allogeneic hematopoietic stem cell transplantation (2010)
  • Author(s): Motoki N, Shimizu T, Akazawa Y, Saito S, Tanaka M, Yanagisawa R, Motoki H, Nakazawa Y, Sakashita K, Iwasaki Y, Shiohara M, Koike K
  • Journal Title: Pediatr Transplant Volume: 14 Pages: 986-92
  • Peer Reviewed
• [Journal Article] Long-term survival after non-intensive chemotherapy in some juvenile myelomonocytic leukemia patients with CBL mutations, and the possible presence of normal individuals with the mutations (2010)
  • Author(s): Matsuda K, Taira C, Sakashita K, Saito S, Tanaka-Yanagisawa M, Yanagisawa R, Nakazawa Y, Shiohara M, Fukushima K, Oda M, Honda T, Nakahata T, Koike K
  • Journal Title: Blood Volume: 115 Pages: 5429-31
  • Peer Reviewed
• [Journal Article] Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan Anemia (2010)
  • Author(s): Konno Y, Toki T, Tandai S, Xu G, Wang R, Terui K, Ohga S, Hara T, Hama A, Kojima S, Hasegawa D, Kosaka Y, Yanagisawa R, Koike K, Kanai R, Imai T, Hongo T, Park MJ, Sugita K, Ito E
  • Journal Title: Haematologica Volume: 95 Pages: 1293-9
  • Peer Reviewed
• [Journal Article] Polymyxin-direct hemoperfusion for sepsisinduced multiple organ failure (2010)
  • Author(s): Hirabayashi K, Shiohara M, Saito S, Tanaka M, Yanagisawa R, Tsuruta G, Fukuyama T, Hidaka Y, Nakazawa Y, Shimizu T, Sakashita K, Koike K
  • Journal Title: Pediatr Blood Cancer Volume: 55 Pages: 202-5
  • Peer Reviewed
• [Journal Article] Low toxicity of a conditioning with 8-Gy total body irradiation, fludarabine and cyclophosphamide as preparative regimen for allogeneic hematopoietic stem cell transplantation in pediatric hematological malignancies.Pediatric Transplantation, 2009 13: 737-45. (2010)
  • Author(s): Hirabayashi K, Shiohara M, Koike K, et, al.
  • Journal Title: Pediatr Blood Cancer Volume: 55 Pages: 202-5
  • Peer Reviewed
• [Journal Article] Quantitative assessment of PTPN11 or RAS mutations at the neonatal period and during the clinical course in patients with juvenile myelomonocytic leukaemia (2009)
  • Author(s): Matsuda K, Sakashita K, Taira C, Tanaka-Yanagisawa M, Yanagisawa R, Shiohara M, Kanegane H, Hasegawa D, Kawasaki K, Endo M, Yajima S, Sasaki S, Kato K, Koike K, Kikuchi A, Ogawa A, Watanabe A, Sotomatsu M, Nonoyama S, Koike K
  • Journal Title: Br J Haematol Volume: 141 Pages: 567-75
  • Peer Reviewed
• [Journal Article] Ela2 mutations and clinical manifestations in familial congenital neutropenia (2009)
  • Author(s): Shiohara M, Shigemura T, Saito S, Tanaka M, Yanagisawa R, Sakashita K, Asada H, Ishii E, Koike K, Chin M, Kobayashi M, Koike K
  • Journal Title: J Pediatr Hematol Oncol Volume: 31 Pages: 319-24
  • Peer Reviewed
• [Journal Article] Cryptic insertion into 11q23 of MLLT10 on 10p12 not involved in t(1 ; 15 ; 11 ; 10)(p36 ; q11 ; q23 ; q24) generated MLL/MLLT10 fusion transcript in infant acute biphenotypic leukemia : application of genomic MLL rearrangement to quantification of minimal residual disease (2009)
  • Author(s): Matsuda K, Tanaka M, Araki S, Yanagisawa R, Yamauchi K, Koike K
  • Journal Title: Cancer Genet Cytogenet. Volume: 190 Pages: 113-20
  • Peer Reviewed
• [Journal Article] Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia (2009)
  • Author(s): Yoshida N, Yagasaki H, Xu Y, Matsuda K, Yoshimi A, Takahashi Y, Hama A, Nishio N, Muramatsu H, Watanabe N, Matsumoto K, Kato K, Ueyama J, Inada H, Goto H, Yabe M, Kudo K, Mimaya J, Kikuchi A, Manabe A, Koike K, Kojima S
  • Journal Title: Pediatr Res Volume: 65 Pages: 334-40
  • Peer Reviewed
• [Journal Article] Low toxicity of a conditioning with 8-Gy total body irradiation, fludarabine and cyclophosphamide as preparative regimen for allogeneic hematopoietic stem cell transplantation in pediatric hematological malignancies (2009)
  • Author(s): Yanagisawa R, Nakazawa Y, Sakashita K, Tanaka M, Shikama N, Kamijo T, Shiohara M, Koike K
  • Journal Title: Pediatric Transplantation Volume: 13 Pages: 737-45
  • NAID: 120007110436
  • Peer Reviewed
• [Journal Article] Urinary excretion of ganciclovir contributes to improvement of adenovirus-associated hemorrhagic cystitis after allogeneic bone marrow transplantation (2009)
  • Author(s): Nakazawa Y, Suzuki T, Fukuyama T, Katsuyama Y, Tanaka M, Yanagisawa R, Sakashita K, Shiohara M, Koike K
  • Journal Title: Pediatric Transplantation Volume: 13 Pages: 632-5
  • Peer Reviewed
• [Journal Article] Quantitative assessment of PTPN11 or RAS mutations at the neonatal period and during the clinical course in patients with juvenile myelomonocytic leukaemia. (2009)
  • Author(s): Matsuda K, Sakashita K, Taira C, Tanaka-Yanagisawa M, Koike K, et al.
  • Journal Title: Br J Haematol 141 Pages: 567-575
  • Peer Reviewed
• [Journal Article] Cryptic insertion into 11q23 of MLLT10 on 10p12 not involved in t (1 ; 15 ; 11 ; 10)(p36 ; q11 ; q23 ; q24) generated MLL/MLLT10 fusion transcript in infant acute biphenotypic leukemia : application of genomic MLL rearrangement to quantification of minimal residual disease. (2009)
  • Author(s): Matsuda K, Tanaka M, Koike K, et al.
  • Journal Title: Cancer Genet Cytogenet. 190 Pages: 113-120
  • Peer Reviewed
• [Journal Article] Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia. (2009)
  • Author(s): Yoshida N, Yagasaki H, Koike K, et al.
  • Journal Title: Pediatr Res 512 Pages: 334-340
  • Peer Reviewed
• [Journal Article] Low toxicity of a conditioning with 8-Gy total body irradiation, fludarabine and cyclophosphamide as preparative regimen for allogeneic he matopoietic stem cell transplantation in pediatric hematological malignancies. Pediatric Transplantation, 2009 13 : 737-45. (2009)
  • Author(s): Yanagisawa R, Nakazawa Y, Koike K, et al.
  • Journal Title: Pediatric Transplantation 13 Pages: 737-745
  • Peer Reviewed
• [Journal Article] Telecommunication system for children undergoing stem cell transplantation
  • Author(s): Higuchi K, Nakazawa Y, Sakata N, Takizawa M, Ohso K, Tanaka M, Yanagisawa R, Koike K
  • Journal Title: Pediatr Int. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Long-term survival after non-intensive chemotherapy in some juvenile myelomonocytic leukemia patients with CBL mutations, and the possible presence of normal individuals with the mutations
  • Author(s): Matsuda K, Taira C, Sakashita K, Koike K, et al.
  • Journal Title: Blood (in press)
  • Peer Reviewed
• [Journal Article] Engraftment syndrome, but not acute graft-versus-host disease, younger age, CYP3A5 or MDR1 polymorphisms, increases tacrolimus clearance in pediatric hematopoietic stem cell transplantation.
  • Author(s): Yanagisawa R, Katsuyama Y, Shigemura T, Saito S, Koike K, et al.
  • Journal Title: Bone Marrow Transplantation (in press)
  • Peer Reviewed
• [Presentation] トランスポゾンを用いた慢性肉芽腫症に対する新たな遺伝子治療法の開発 (2012)
  • Author(s): 重村倫成、中沢洋三、松田和之、小池健一
  • Organizer: 第115回日本小児科学会学術集会
  • Place of Presentation: 福岡
• [Presentation] チェルノブイリ原発事故と福島第一原発事故-人体への影響- (2011)
  • Author(s): 小池健一
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 前橋
• [Presentation] T細胞性悪性リンパ腫再発に対してネララビント臍帯血移植を併用した1例 (2011)
  • Author(s): 柳沢俊光、小池健一, 他
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 前橋
• [Presentation] PiggyBacトランスポゾン法を用いて遺伝子修復したX連鎖慢性肉芽腫症患者T細胞からのiPS細胞の樹立 (2011)
  • Author(s): 重村倫成、中沢洋三、小池健一, 他
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 前橋
• [Presentation] FTA cards for genetic evaluation of childhood ALL in Iraq (2011)
  • Author(s): Al Kzayer, Sakashita K, Koike K, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] 小児同種造血幹細胞移植後再発の予後に関する検討 (2011)
  • Author(s): Sakashita K, Koike K, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] チェルノブイリ原発事故と福島第一原発事故-人体への影響- (2011)
  • Author(s): 小池健一
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 前橋(招待講演)
• [Presentation] FTA cards for genetic evaluation of childhood ALL in Iraq (2011)
  • Author(s): Al Kzayer, Sakashita K, Koike K, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] 小児同種造血幹細胞移植後再発の予後に関する検討 (2011)
  • Author(s): Sakashita K, Koike K, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] 教育セミナー小児科領域におけるITの活用 (2010)
  • Author(s): 小池健一
  • Organizer: 日本小児科学会
  • Place of Presentation: 盛岡市
  • Year and Date: 2010-04-23
• [Presentation] 血液教育セッション2:若年性骨髄単球性白血病の遺伝子異常とMRD検索 (2009)
  • Author(s): 小池健一
  • Organizer: 日本小児血液学会
  • Year and Date: 2009-11-27
• [Presentation] 若年性骨髄単球性白血病の遺伝子異常とMRD検索 (2009)
  • Author(s): 小池健一、松田和之
  • Organizer: 第51回日本小児血液学会総会
  • Place of Presentation: 東京
• [Presentation] 遺伝子変異特異的定量PCR法を用いた若年性骨髄単球性白血病の発症時期の検討 (2009)
  • Author(s): 松田和之、小池健一, 他
  • Organizer: 第71回本血液学会学術集会
  • Place of Presentation: 京都
• [Book] 標本に学ぶ血液疾患症例、2種類の染色体異常を認めた若年性慢性単球性白血病-juvenile myelomonocytic leukemia(JMML)の1例 (2012)
  • Author(s): 小池健一、松崎聡、松田和之
  • Publisher: 医薬ジャーナル社
• [Book] 標本に学ぶ血液疾患症例 (2012)
  • Author(s): 小池健一、松崎聡、松田和之
  • Publisher: 医薬ジャーナル社
• [Book] 血液・腫瘍科、若年性慢性骨髄単球性白血病の分子病態解明の進歩 (2010)
  • Author(s): 小池健一, ほか
  • Publisher: 科学評論社