Development of novel molecular targeted therapy for juvenile myelomonocytic leukemia

• Project/Area Number: 24390262
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nagoya University
• Principal Investigator: KOJIMA Seiji 名古屋大学, 医学(系)研究科(研究院), 教授 (20313992)
• Co-Investigator(Kenkyū-buntansha): TAKAHASHI Yoshiyuki 名古屋大学, 大学院医学系研究科, 准教授 (40432273) ; 嶋田 明 岡山大学, 大学病院, 講師 (70391836)
• Co-Investigator(Renkei-kenkyūsha): SHIMADA Akira 岡山大学, 大学病院, 講師 (70391836)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000); Fiscal Year 2014: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 若年性骨髄単球性白血病 / 原因遺伝子 / 白血病幹細胞 / エピジェネティクス / エクソーム解析 / 若年型骨髄単球性白血病 / RASシグナル経路 / 全エクソーム解析 / SETBP1 / メチル化解析

Outline of Final Research Achievements

Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric myeloid malignancy, and the development of novel molecular target therapy is strongly warranted. Here, we analyzed 92 JMML patients with next-generation sequencing technique, and identified that patients with newly identified SETBP1 and JAK3 mutations as secondary genetic events showed inferior survival rates (Sakaguchi H, et al, Nature Genetics 2013).
In addition, we assessed the effects of tyrosine kinase inhibitor (Dasatinib) and MEK inhibitor (MEK162) for bone marrow mononuclear cells from JMML patients. Dasatinib and MEK162 are significantly suppressed the colony forming of JMML cells. Flowcytometry-based BrdU/SubG1 analysis revealed that these drugs significantly suppress cell proliferation and induce cell apoptosis. Our findings support that Dasatinib and MEK inhibitor would be promising agents for treatment of JMML patients.

Research Products

• [Journal Article] Germline mutation of CBL is associated with moyamoya disease in a child with juvenile myelomonocytic leukemia and Noonan syndrome-like disorder. (2015)
  • Author(s): Hyakuna N, Muramatsu H, Higa T, Chinen Y, Wang X, Kojima S.
  • Journal Title: Pediatr Blood Cancer Volume: 62 Issue: 3 Pages: 542-544
  • DOI: 10.1002/pbc.25271
  • Peer Reviewed
• [Journal Article] Choreito formula for BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. (2015)
  • Author(s): Kawashima N, Ito Y, Sekiya Y, Narita A, Okuno Y, Muramatsu H, Irie M, Hama A, Takahashi Y, Kojima S.
  • Journal Title: Biol Blood Marrow Transplant Volume: 21 Issue: 2 Pages: 319-325
  • DOI: 10.1016/j.bbmt.2014.10.018
  • Peer Reviewed
• [Journal Article] Aldehyde dehydrogenase-2 polymorphism contributes to the progression of bone marrow failure in children with idiopathic aplastic anaemia. (2015)
  • Author(s): Kawashima N, Narita A, Wang X, Xu Y, Sakaguchi H, Doisaki S, Muramatsu H, Hama A, Nakanishi K, Takahashi Y, Kojima S.
  • Journal Title: Br J Haematol. Volume: 168 Issue: 3 Pages: 460-463
  • DOI: 10.1111/bjh.13122
  • Peer Reviewed
• [Journal Article] Clinical characteristics of 15 children with juvenile myelomonocytic leukaemia who developed blast crisis: MDS Committee of Japanese Society of Paediatric Haematology/Oncology. (2014)
  • Author(s): Honda Y, Tsuchida M, Zaike Y, Masunaga A, Yoshimi A, Kojima S, Ito M, Kikuchi A, Nakahata T, Manabe A.
  • Journal Title: Br J Haematol Volume: in press Issue: 5 Pages: 682-687
  • DOI: 10.1111/bjh.12796
  • Peer Reviewed
• [Journal Article] RUNX1 mutation associated with clonal evolution in relapsed pediatric acute myeloid leukemia with t(16;21)(p11;q22). (2014)
  • Author(s): Ismael O, Shimada A, Elmahdi S, Elshazley M, Muramatsu H, Hama A, Takahashi Y, Yamada M, Yamashita Y, Horibe K, Kojima S.
  • Journal Title: Int J Hematol Volume: 99 Issue: 2 Pages: 169-174
  • DOI: 10.1007/s12185-013-1495-5
  • Peer Reviewed
• [Journal Article] Long-term outcome after immunosuppressive therapy with horse or rabbit antithymocyte globulin and cyclosporine for severe aplastic anemia in children. (2014)
  • Author(s): Jeong DC, Chung NG, Cho B, Zou Y, Ruan M, Takahashi Y, Muramatsu H, Ohara A, Kosaka Y, Yang W, Kim HK, Zhu X, Kojima S.
  • Journal Title: Haematologica Volume: 99 Issue: 4 Pages: 664-671
  • DOI: 10.3324/haematol.2013.089268
  • Peer Reviewed
• [Journal Article] Treatment of aplastic anemia in children (2014)
  • Author(s): Kojima S.
  • Journal Title: Rinsho Ketsueki. Volume: 55 Pages: 1769-1776
  • NAID: 130004696069
  • Peer Reviewed
• [Journal Article] Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia. (2014)
  • Author(s): Sakaguchi H, Nishio N, Hama A, Kawashima N, Wang X, Narita A, Doisaki S, Xu Y, Muramatsu H, Yoshida N, Takahashi Y, Kudo K, Moritake H, Nakamura K, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Kojima S; Japan Childhood Aplastic Anemia Study Group.
  • Journal Title: Haematologica Volume: 99 Issue: 8 Pages: 1312-1316
  • DOI: 10.3324/haematol.2013.091165
  • Peer Reviewed
• [Journal Article] Clinical course of juvenile myelomonocytic leukemia in the blast crisis phase treated by acute myeloid leukemia-oriented chemotherapy and allogeneic hematopoietic stem cell transplantation. (2014)
  • Author(s): Ueda S, Sakata N, Muramatsu H, Sakaguchi H, Wang X, Xu Y, Kojima S, Yamaguchi T, Higa T, Takemura T.
  • Journal Title: Int J Hematol. Volume: 100 Issue: 5 Pages: 502-506
  • DOI: 10.1007/s12185-014-1638-3
  • Peer Reviewed
• [Journal Article] Immunosuppressive therapy with horse anti-thymocyte globulin and cyclosporine as treatment for fulminant aplastic anemia in children. (2014)
  • Author(s): Yagasaki H, Shichino H, Ohara A, Kobayashi R, Yabe H, Ohga S, Hamamoto K, Ohtsuka Y, Shimada H, Inoue M, Muramatsu H, Takahashi Y, Kojima S.
  • Journal Title: Ann Hematol. Volume: 93 Issue: 5 Pages: 747-752
  • DOI: 10.1007/s00277-013-1984-x
  • Peer Reviewed
• [Journal Article] First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy. (2014)
  • Author(s): Yoshida N, Kobayashi R, Yabe H, Kosaka Y, Yagasaki H, Watanabe K, Kudo K, Morimoto A, Ohga S, Muramatsu H, Takahashi Y, Kato K, Suzuki R, Ohara A, Kojima S
  • Journal Title: Haematologica. Volume: 99 Issue: 12 Pages: 1784-1791
  • DOI: 10.3324/haematol.2014.109355
  • Peer Reviewed
• [Journal Article] Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients. (2013)
  • Author(s): Hira A, Yoshida K
  • Journal Title: Blood Volume: 122 Issue: 18 Pages: 3206-3209
  • DOI: 10.1182/blood-2013-06-507962
  • Peer Reviewed
• [Journal Article] Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia. (2013)
  • Author(s): Kar SA, Jankowska A, Makishima H, Visconte V, Jerez A, Sugimoto Y, Muramatsu H, Traina F, Afable M, Guinta K, Tiu RV, Przychodzen B, Sakaguchi H, Kojima S, Sekeres MA, List AF, McDevitt MA, Maciejewski JP.
  • Journal Title: Haematologica Volume: 98(1) Issue: 1 Pages: 107-113
  • DOI: 10.3324/haematol.2012.064048
  • Peer Reviewed
• [Journal Article] ACTN1 Mutations Cause Congenital Macrothrombocytopenia (2013)
  • Author(s): 國島伸治、吉田健一
  • Journal Title: Am J Hum Genet Volume: 92 Issue: 3 Pages: 431-438
  • DOI: 10.1016/j.ajhg.2013.01.015
  • Peer Reviewed
• [Journal Article] Somatic SETBP1 mutations in myeloid malignancies. (2013)
  • Author(s): Makishima H, Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 8 Pages: 942-946
  • DOI: 10.1038/ng.2696
  • Peer Reviewed
• [Journal Article] Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. (2013)
  • Author(s): Sakaguchi H, Yoshida K
  • Journal Title: Nature Genet. Volume: 46 Issue: 8 Pages: 937-941
  • DOI: 10.1038/ng.2698
  • Peer Reviewed
• [Journal Article] The landscape of somatic mutations in Down syndrome-related myeloid disorders. (2013)
  • Author(s): Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 11 Pages: 1293-1200
  • DOI: 10.1038/ng.2759
  • Peer Reviewed
• [Journal Article] Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia. (2013)
  • Author(s): Yoshimi A, Kamachi Y, Kojima S and et al.
  • Journal Title: Pediatr Blood Cancer. Volume: 60 Issue: 5 Pages: 836-841
  • DOI: 10.1002/pbc.24359
  • Peer Reviewed
• [Journal Article] Rabbit antithymocyte globulin and cyclosporine as first-line therapy for children with acquired aplastic anemia (2012)
  • Author(s): Takahashi Y, Muramatsu H, Sakata N, Hyakuna N, Hamamoto K, Kobayashi R, Ito E, Yagasaki H, Ohara A, Kikuchi A, Morimoto A, Yabe H, Kudo K, Watanabe K, Ohga S, Kojima S
  • Journal Title: Blood Volume: 121(5) Issue: 5 Pages: 862-3
  • DOI: 10.1182/blood-2012-11-465633
  • Peer Reviewed
• [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.
  • Journal Title: Br J Haematol Volume: 157(5) Pages: 647-50
  • Peer Reviewed
• [Journal Article] Current Management of Juvenile Myelomonocytic Leukemia and the Impact of RAS Mutations. (2012)
  • Author(s): Yoshida N.
  • Journal Title: Paediatr Drugs Volume: 14(3) Pages: 157-63
  • Peer Reviewed
• [Journal Article] Loss of heterozygosity in 7q myeloid disorders : clinical associations and genomic pathogenesis. (2012)
  • Author(s): Jerez A.
  • Journal Title: Blood Volume: 119(25) Pages: 6109-17
  • Peer Reviewed
• [Journal Article] De novo childhood myelodysplastic/myeloproliferative disease with unique molecular characteristics. (2012)
  • Author(s): Ismael O.
  • Journal Title: Br J Haematol Volume: 158(1) Pages: 129-37
  • 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: Br J Haematol Volume: 158(5) Pages: 657-661
  • Peer Reviewed
• [Journal Article] Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomon ocytic leukemia. (2012)
  • Author(s): Doisaki S.
  • Journal Title: Blood Volume: 120(7) Pages: 1485-8
  • Peer Reviewed
• [Journal Article] Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia. (2012)
  • Author(s): Yoshimi A.
  • Journal Title: Pediatr Blood Cancer Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Mutational analysis of RNA splicing machinery components in 206 children with myeloid malignancies. (2012)
  • Author(s): Sakaguchi H.
  • Journal Title: Leuk Res. Volume: 36(12)
  • Peer Reviewed
• [Journal Article] Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia. (2012)
  • Author(s): Abu Kar S.
  • Journal Title: Haematologica Volume: 98(1) Pages: 107-13
  • Peer Reviewed
• [Presentation] Generation of Cell Lines Harboring SETBP1 Mutations By the Crispr/Cas9 system (2014)
  • Author(s): Kawashima N, Okuno Y, Sekiya Y, Wang X, Xu Y, Narita A, Doisaki S, Kamei M, Muramatsu H, Irie M, Hama A, Takahashi Y, Kojima S.
  • Organizer: 56th ASH Annual Meeting and Exposition
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-12-08
• [Presentation] Screening of candidate RAS pathway-related genes in juvenile myelomonocytic leukemia using CRISPR/Cas system. (2014)
  • Author(s): Okuno Y, Kawashima N, Muramatsu H, Hama A, Takahashi Y, Kojima S
  • Organizer: 第56回日本小児血液・がん学会学術集会
  • Place of Presentation: 岡山県岡山市（ 岡山コンベンションセンター）
  • Year and Date: 2014-11-28
• [Presentation] Mutational analysis of RRAS in Japanese juvenile myelomonocytic leukemia patient (2014)
  • Author(s): Wang X, Nishikawa E, Muramatsu H, Okuno Y, Sekiya Y, Kawashima N, Xu Y, Narita A, Doisaki S, Hama A, Takahashi Y, Kojima S.
  • Organizer: 第56回日本小児血液・がん学会学術集会
  • Place of Presentation: 岡山県岡山市（ 岡山コンベンションセンター）
  • Year and Date: 2014-11-28
• [Presentation] 骨髄移植後に急性散在性脳脊髄炎をきたした若年性骨髄単球性白血病の一例 (2014)
  • Author(s): 西川英里、高橋義行、関屋由子、川島希、奥野友介、成田敦、土居崎小夜子、入江正寛、亀井美智、村松秀城、濱麻人、小島勢二
  • Organizer: 第56回日本小児血液・がん学会学術集会
  • Place of Presentation: 岡山県岡山市（ 岡山コンベンションセンター）
  • Year and Date: 2014-11-28
• [Presentation] Quantification of GM-CSF hypersensitivity and suppression by an MEK1/2 inhibitor of JMML (2014)
  • Author(s): 川島 希、奥野友介、村松秀城、入江正寛、濱麻人、高橋義行、小島勢二
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪府大阪市（ 大阪国際会議場）
  • Year and Date: 2014-11-01
• [Presentation] Current results and experiences of multi-center clinical study for SAA HSCT in Japan (2014)
  • Author(s): Kojima S
  • Organizer: The 19th congress of APBMT
  • Place of Presentation: 杭州 中国
  • Year and Date: 2014-10-15
  • Invited
• [Presentation] 小児がん診療、集約化への道筋 (2014)
  • Author(s): 小島勢二
  • Organizer: 日本癌治療学会学術集会
  • Place of Presentation: 神奈川県横浜市（ パシフィコ横浜）
  • Year and Date: 2014-08-28
  • Invited
• [Presentation] 小児における血液疾患の診断 (2014)
  • Author(s): 小島勢二
  • Organizer: 日本検査血液学会学術集会
  • Place of Presentation: 宮城県仙台市（ 仙台国際センター）
  • Year and Date: 2014-07-20
  • Invited
• [Presentation] Recent Progress in Diagnosis and Treatment of Aplastic Anemia in Children (2014)
  • Author(s): Kojima S.
  • Organizer: South China Hematology Summit
  • Place of Presentation: 広州 中国
  • Year and Date: 2014-07-19
  • Invited
• [Presentation] Recent Progress in Diagnosis and Treatment of Aplastic Anemia in Children (2014)
  • Author(s): Kojima S.
  • Organizer: Expert Meeting at Wuhan Union Hospital
  • Place of Presentation: 武漢 中国
  • Year and Date: 2014-07-15
  • Invited
• [Presentation] Clonal Evolution from Aplastic Anemia to Myelodysplastic Syndrome with Monosomy7. (2013)
  • Author(s): Kojima S.
  • Organizer: 7th International Congress on Shwachman-Diamond Syndrome.
  • Place of Presentation: Toronto, Canada
  • Invited
• [Presentation] Whole exome analysis reveals spectrum of gene mutations in juvenile myelomonocytic leukemia. (2012)
  • Author(s): Muramatsu H.
  • Organizer: 54th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Georgia World Congress Center (Atlanta, USA)
  • Year and Date: 2012-12-09
• [Presentation] CBL変異を伴う若年性骨髄単球性白血病9例の臨床像の特徴 (2012)
  • Author(s): 坂口大俊, 他
  • Organizer: 第54回日本小児血液・がん学会学術集会
  • Place of Presentation: パシフィコ横浜会議センター、横浜
  • Year and Date: 2012-11-30
• [Presentation] Clinical significance of aberrant DNA methylation in juvenile myelomon ocytic leukemia. (2012)
  • Author(s): Sakaguchi H.
  • Organizer: 6th International Symposium on MDS and Bone Marrow Failure Syndromes in Childhood
  • Place of Presentation: Diplomat Hotel Prague(プラハ、チェコ)
  • Year and Date: 2012-11-07
• [Presentation] Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomon ocytic leukemia. (2012)
  • Author(s): Muramatsu H.
  • Organizer: 6th International Symposium on MDS and Bone Marrow Failure Syndromes in Childhood
  • Place of Presentation: Diplomat Hotel Prague(プラハ、チェコ)
  • Year and Date: 2012-11-07
• [Presentation] Comprehensive genetic analysis by deep sequencing in juvenile myelomonocytic leukemia. (2012)
  • Author(s): Muramatsu H.
  • Organizer: 6th International Symposium on MDS and Bone Marrow Failure Syndromes in Childhood
  • Place of Presentation: Diplomat Hotel Prague(プラハ、チェコ)
  • Year and Date: 2012-11-07
• [Presentation] JAK2 V617F mutation in pediatric myeloproliferative neoplasm. (2012)
  • Author(s): Shimada A.
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 2012-10-20
• [Presentation] The Asia Pacific prospective randomised study of standard vs low dose rabbit ATG in aplastic anemia.
  • Author(s): Kojima S.
  • Organizer: 39th Annual Meeting of the EBMT.
  • Place of Presentation: London, UK
  • Invited
• [Presentation] Clinical and genetic characterization of 17 Juvenile myelomonocytic leukemia patients with c-CBL mutations.
  • Author(s): Muramatsu H, Sakaguchi H, Xu Y, Yoshida K, Okuno Y, Hama A, Takahashi Y, Makishima H, Maciejewski J.P, Ogawa S, Kojima S.
  • Organizer: The 12th International Symposium on Myelodysplastic Syndromes.
  • Place of Presentation: Berlin, Germany
• [Presentation] Molecular Spectrum of Juvenile Myelomonocytic Leukemia Identified by Whole exome sequencing.
  • Author(s): Sakaguchi H, Muramatsu H, Yoshida K, Okuno Y, Shiraishi Y, Sanada M, Chiba K, Tanaka H, Makishima H, Wang X, Xu Y, Doisak Si, Hama A, Nakanishi K, Takahashi Y, Yoshida N, Maciejewski JP, Miyano S, Ogawa S, Kojima S.
  • Organizer: The 18th Congress of EHA.
  • Place of Presentation: Stockholm, Sweden
• [Presentation] Aplastic Anemia : Therapeutic updated in HSCT.
  • Author(s): Kojima S.
  • Organizer: 2013 International Forum on Bone Marrow Failure.
  • Place of Presentation: Tianjin, China
  • Invited
• [Presentation] Alternative Donor Transplant for Aplastic Anemia.
  • Author(s): Kojima S.
  • Organizer: The 3rd International Annual Updates on Breathroughs in Hematology.
  • Place of Presentation: Bangkok, Thailand
  • Invited
• [Presentation] Haploidentical vs Matched Unrelated Donor Transplant.
  • Author(s): Kojima S.
  • Organizer: The 3rd International Annual Updates on Breathroughs in Hematology.
  • Place of Presentation: Bangkok, Thailand
  • Invited
• [Presentation] Reports from APBMT Working Group.
  • Author(s): Kojima S.
  • Organizer: 18th APBMT 2013.
  • Place of Presentation: Ho Chi Minh, Vietnam
  • Invited
• [Presentation] Clinical and Genetic Characterization Of Patients With C-CBL Mutated Juvenile Myelomonocytic Leukemia By Whole-Exome/Deep Sequencing.
  • Author(s): Muramatsu H, Sakaguchi H, Wang X, Yoshida K, Okuno Y, Sanada M, Xu Y, Doisaki S, Narita A, Kawashima N, Hama A, Takahashi Y, Yoshida N, Shiraishi Y, Chiba K, Tanaka H, Makishima H, Maciejewski J.P, Miyano S, Ogawa S, Kojima S.
  • Organizer: The 55th ASH Annual Meeting and Exposition.
  • Place of Presentation: New Orleans, USA
• [Presentation] Aberrant DNA Methylation Is Associated With Poor Outcomes In Juvenile Myelomonocytic Leukemia.
  • Author(s): Sakaguchi H, Muramatsu H, Wang X, Xu Y, Hibi Y, Kawashima N, Narita A, Doisaki S, Yoshida N, Hama A, Takahashi Y, Makishima H, Yamada K, Maciejewski JP, Kojima S.
  • Organizer: The 55th ASH Annual Meeting and Exposition.
  • Place of Presentation: New Orleans, USA