The role of hematopoietic microenvironment in the pathogenesis and spontaneous remission of fetal leukemia

• Project/Area Number: 15K09729
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Embryonic/Neonatal medicine
• Research Institution: Tokyo Dental College
• Principal Investigator: Miyauchi Jun 東京歯科大学, 歯学部, 客員教授 (20146707)
• Co-Investigator(Kenkyū-buntansha): 川口 裕之 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 小児科学, 准教授 (00313130) ; 宮下 俊之 北里大学, 医学部, 教授 (60174182)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ダウン症候群 / 胎児性白血病 / 一過性白血病 / 自然治癒 / 造血微小環境 / 胎児造血 / 造血因子 / サイトカイン / 肝臓 / 肝芽細胞 / 乳児白血病

Outline of Final Research Achievements

Transient leukemia (TL) in neonates with Down syndrome is a unique fetal leukemia, which arises in fetal liver and spontaneously resolves after birth. Prenatal hematopoietic microenvironment is thought to be relevant to the pathogenesis of TL. We analyzed the functions of hepatoblasts, one of the major constituents of fetal liver hematopoietic microenvironment, on TL cells by using co-culture system. The hepatoblasts produced several human hematopoietic growth factors, including stem cell factor, and stimulated growth and induced megakaryocytic differentiation of TL cells. These data indicate that hematopoietic growth factors produced from fetal liver hematopoietic microenvironment play an important role in the pathogenesis of TL.

Research Products

• [Journal Article] Role of monocyte chemoattractant protein-1 in liver fibrosis with transient myeloproliferative disorder in down syndrome (2018)
  • Author(s): Kobayashi Kenichiro、Yoshioka Takako、Miyauchi Jun、Nakazawa Atsuko、Kiyokawa Nobutaka、Maihara Toshiro、Usami Ikuya
  • Journal Title: Hepatology Communications Volume: 2 Issue: 3 Pages: 230-236
  • DOI: 10.1002/hep4.1150
  • Peer Reviewed / Open Access
• [Journal Article] Monocyte chemoattractant protein-1 (MCP-1) as a potential therapeutic target and a noninvasive biomarker of liver fibrosis associated with transient myeloproliferative disorder in Down syndrome (2017)
  • Author(s): Kobayashi K, Yoshioka T, Miyauchi J, Nakazawa A, Yamazaki S, Ono H, Tatsuno M, Iijima K, Takahashi C, Okada Y, Teranishi K, Matsunaga T, Matsushima C, Inagaki M, Suehiro M, Suehiro S, Nishitani M, Kubota H, Iio J, Nishida Y, Katayama T, Takada N, Watanabe K, Yamamoto T, Yasumizu R, Matsuoka K, Ohki K, et al.
  • Journal Title: J Pediatr Hematol Oncol Volume: 39
  • Peer Reviewed / Open Access
• [Journal Article] ダウン症候群関連骨髄増殖性疾患と造血微小環境 (2017)
  • Author(s): 宮内 潤
  • Journal Title: 東京歯科大学会誌 Volume: 117 Pages: 93-103
  • Peer Reviewed
• [Journal Article] L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease. (2017)
  • Author(s): Yanagisawa H, Ishii T, Endo K, Kawakami E, Nagao K, Miyashita T, Akiyama K, Watabe K, Komatsu M, Yamamoto D, Eto Y.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 15994-15994
  • DOI: 10.1038/s41598-017-15305-9
  • Peer Reviewed / Open Access
• [Journal Article] The serine 106 residue within the N-terminal transactivation domain is crucial for Oct4 function in mice (2017)
  • Author(s): Mitani A, Fukuda A, Miyashita T, Umezawa A, Akutsu H
  • Journal Title: zygote Volume: 25 Issue: 2 Pages: 197-204
  • DOI: 10.1017/s0967199417000053
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cytomegalovirus infection- and dasatinib-induced proteinuria in Ph+ALL (2017)
  • Author(s): Kawaguchi Hiroyuki、Tamura Yoshiteru、Suzuki Shuichi、Asano-Murakoshi Takako、Nonoyama Shigeaki
  • Journal Title: Pediatr Int Volume: 59 Issue: 6 Pages: 740-741
  • DOI: 10.1111/ped.13251
  • Peer Reviewed
• [Journal Article] CD66c (KOR-SA3544) antigen expression of leukemic blasts in pediatric acute myeloid leukemia with TLS/FUS-ERG fusion transcript (2017)
  • Author(s): Kobayashi K.、Isobe K.、Hanada R.、Kawaguchi H.、Iwata T.、Kawamura M.
  • Journal Title: International Journal of Laboratory Hematology Volume: 39 Issue: 6
  • DOI: 10.1111/ijlh.12714
  • Peer Reviewed
• [Journal Article] A pediatric case of acute megakaryocytic leukemia with double chimeric transcripts of CBFA2T3-GLIS2 and DHH-RHEBL1 (2017)
  • Author(s): Mitsui-Sekinaka Kanako、Sekinaka Yujin、Ogura Yumi、Honda Mamoru、Ohyama Ryo、Oyama Chigusa、Isobe Kiyotaka、Mori Makiko、Arakawa Yuki、Koh Katsuyoshi、Hanada Ryoji、Nonoyama Shigeaki、Kawaguchi Hiroyuki
  • Journal Title: Leuk Lymphoma Volume: Epub ahead of print Issue: 6 Pages: 1-3
  • DOI: 10.1080/10428194.2017.1387901
  • Peer Reviewed
• [Journal Article] 川崎病罹患を契機に診断された自己免疫性好中球減少症の1例 (2017)
  • Author(s): 廣瀬 文, 川村 陽一, 金井 貴志, 辻田 由喜, 岸本 健寛, 川口 裕之, 竹下 誠一郎, 野々山 恵章
  • Journal Title: 防衛医科大学校雑誌 Volume: 42 Pages: 34-38
• [Journal Article] Somatic mosaicism containing double mutations in PTCH1 revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome. (2017)
  • Author(s): Ikemoto, Y., Takayama, Y., Fujii, K., Masuda, M., Kato, C., Hatsuse, H., Fujitani, K., Nagao, K., Kameyama, K., Ikehara, H., Toyoda, M., Umezawa, A. and Miyashita, T.
  • Journal Title: Journal of Medical Genetics Volume: － Issue: 8 Pages: 579-584
  • DOI: 10.1136/jmedgenet-2016-104490
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clear cell adenocarcinoma arising from adenomyotic cyst: a case report and literature review. (2016)
  • Author(s): Baba A, Yamazoe S, Dogru M, Ogawa M, Takamatsu K, Miyauchi J
  • Journal Title: J Obstet Gynecol Res Volume: 42 Issue: 2 Pages: 217-223
  • DOI: 10.1111/jog.12866
  • Peer Reviewed
• [Journal Article] Juvenile fibroadenoma with features of phyllodes tumor showing intraductal growth and prominent epithelial hyperplasia in an 11-year-old girl (2016)
  • Author(s): Miyauchi J, Yoshida F, Akatsuka S, Nakano M:
  • Journal Title: Human Pathology: Case Reports Volume: 印刷中 Pages: 18-22
  • DOI: 10.1016/j.ehpc.2015.07.001
  • Peer Reviewed / Open Access
• [Journal Article] Anaplastic carcinoma of the pancreas: Case report and literature review of reported cases in Japan. (2016)
  • Author(s): Hoshimoto S, Matsui J, Miyata R, Takigawa Y, Miyauchi J
  • Journal Title: World J Gastroenterol Volume: 22 Issue: 38 Pages: 8631-8637
  • DOI: 10.3748/wjg.v22.i38.8631
  • Peer Reviewed / Open Access
• [Journal Article] 根治的切除が可能であった横行結腸MANECの１例． (2016)
  • Author(s): 浅原史卓、宮内 潤、橋本和彦
  • Journal Title: 日本大腸肛門病学会雑誌 Volume: 69 Pages: 436-440
  • NAID: 130005166011
  • Peer Reviewed
• [Journal Article] Brain morphology in children with nevoid basal cell carcinoma syndrome. (2016)
  • Author(s): Shiohama T, Fuji K, Miyashita T, Mizuochi H, Uchikawa H, Shimojo N
  • Journal Title: Am J Med Genet (Part A) Volume: 173 Pages: 946-952
  • Peer Reviewed
• [Journal Article] Nevoid basal cell carcinoma syndrome caused by splicing mutations in the PTCH1 gene. (2016)
  • Author(s): Kato C, Fujii K, Arai Y, Hatsuse H, Nagao K, Takayama Y, Kameyama K, Fujii K, Miyashita T
  • Journal Title: Fam Cancer Volume: 16 Pages: 131-138
  • Peer Reviewed
• [Journal Article] Gorlin syndrome with an ovarian leiomyoma associated with a PTCH1 second hit. (2016)
  • Author(s): Akizawa Y, Miyashita T, Sasaki R, Nagata R, Aoki R, Ishitani K, Nagashima Y, Matsui H, Saito K
  • Journal Title: Am J Med Genet (Part A) Volume: 170 Pages: 1029-1034
  • Peer Reviewed
• [Journal Article] Gorlin syndrome with an ovarian leiomyoma associated with a PTCH1 second hit (2016)
  • Author(s): Akizawa, Y., Miyashita, T., Sasaki, R., Nagata, R., Aoki, R., Ishitani, K., Nagashima, Y., Matsui, H., Saito, K
  • Journal Title: Am J Med A Volume: 170 Issue: 4 Pages: 1029-1034
  • DOI: 10.1002/ajmg.a.37517
  • Peer Reviewed / Open Access
• [Journal Article] Transient abnormal myelopoiesis of extremely immature infant followed by blast cell resurgence two months later: a case study (2015)
  • Author(s): Nomura Y, Miyauchi J, Ota E, Yanai F, Miyashita T, Terui K, Ito E, Hirose S
  • Journal Title: Jap J Pediatr Hematol/Oncol Volume: 52 Pages: 36-39
  • Peer Reviewed
• [Journal Article] Mirror syndrome associated with fetal transient abnormal myelopoiesis in Down syndrome (2015)
  • Author(s): Kobayashi, Y., Miyoshi, T., Matsuyama, T., Miyauchi, J., Miyashita, T., Ishibashi-Ueda, H. and Yoshimatsu, J.
  • Journal Title: Pathology International Volume: 印刷中 Issue: 8 Pages: 443-445
  • DOI: 10.1111/pin.12291
  • Peer Reviewed / Open Access
• [Journal Article] Pediatric leukemia and hematopoietic microenvironment: Is spontaneous remission due to extrinsic or intrinsic mechanism? (2015)
  • Author(s): Miyauchi J
  • Journal Title: Austin J Pathol Lab Med Volume: 2 Pages: 1013-1013
  • Peer Reviewed / Open Access
• [Journal Article] Predictors of gastric neoplasia in cases negative for Helicobacter pylori antibody and with normal pepsinogen (2015)
  • Author(s): Kishikawa H, Kimura K, Ito A, Asahata K, Takarabe S, Kaida S, Miyauchi J, Miura S, Nishida J
  • Journal Title: Anticancer Res Volume: 35 Pages: 6765-6772
  • Peer Reviewed
• [Journal Article] Chromatin condensation of Xist genomic loci during oogenesis in mice (2015)
  • Author(s): Fukuda, A., Mitani, A., Miyashita, T., Umezawa, A., Akutsu, H
  • Journal Title: Development Volume: 142 Pages: 4049-4055
  • DOI: 10.1242/dev.127308
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A rare case of a symptomatic tumor found in the groin area: An atypical location unexposed to the known causes (2015)
  • Author(s): Toyonaga, E., Hata, H., Nakayama, C., Homma, E., Miyashita, T., Shimizu, H
  • Journal Title: Case Rep. Oncol Volume: 8 Issue: 3 Pages: 536-539
  • DOI: 10.1159/000442148
  • NAID: 120006363266
  • Peer Reviewed / Open Access
• [Journal Article] Confocal microscopy for intracellular co-localization of proteins (2015)
  • Author(s): Miyashita, T
  • Journal Title: Methods in Molecular Biology Volume: 1278 Pages: 515-526
  • DOI: 10.1007/978-1-4939-2425-7_34
  • ISBN: 9781493924240, 9781493924257
  • Peer Reviewed
• [Journal Article] 若年性骨髄単球性白血病 (2015)
  • Author(s): 宮内 潤
  • Journal Title: 臨床検査 Volume: 59 Pages: 990-997
• [Journal Article] PTCH1, PTCH2, SUFU (2015)
  • Author(s): 宮下俊之
  • Journal Title: 日本臨牀 Volume: 増刊号 Pages: 375-379
• [Presentation] MicroRNA analysis in dermal fibroblasts derived from Gorlin syndrome patients (2017)
  • Author(s): Shiohama, T. Fujii, K. Takatani, T. Miyashita, T. Ikehara, H. Fujita, M. Fukuhara, T. Shimojo, N.
  • Organizer: 第59回小児神経学会総会
• [Presentation] 疾患特異的iPS細胞の解析を契機に発見された母斑基底細胞癌症候群のモザイク症例 (2017)
  • Author(s): 宮下 俊之、高山吉永、藤井 克則、梅澤 明弘
  • Organizer: 第23回日本家族性腫瘍学会学術集会
• [Presentation] 母斑基底細胞癌症候群患者由来のiPS細胞に見いだされたPTCH1遺伝子の体細胞モザイク変異 (2017)
  • Author(s): 高山吉永、長尾 和右、宮下 俊之、藤井 克則
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Gorlin症候群責任遺伝子PTCH1のディープシークエンス解析 (2017)
  • Author(s): 増田 木理、兼友裕大、高山吉永、初瀬洋美、藤谷和子、長尾 和右、亀山 孝三、藤井 克則、宮下 俊之
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] CRISPR/Cas9システムを用いたNBCCS疾患モデルiPS細胞の作製 (2017)
  • Author(s): 荒井佑斗、加藤千勢、長尾和右、初瀬洋美、高山吉永、亀山孝三、梅澤 明弘、藤井 克則、宮下 俊之
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] 非定型CMLに対する臍帯血移植後のステロイド抵抗性腸管GVHDに対し、経口ベクロメタゾンとヒト骨髄由来間葉系幹細胞が有効であった男児例 (2017)
  • Author(s): 嶋 晴子、伊藤淳平、一色恭平、関中悠仁、山崎文登、小倉友美、川口裕之、嶋田博之
  • Organizer: 第39回日本造血細胞移植学会総会
• [Presentation] 出生前から機能不全家庭となることが懸念された事例の検討 (2017)
  • Author(s): 川口 裕之, 野々山 恵章
  • Organizer: 第120回日本小児科学会学術集会
• [Presentation] ハイドロキシウレアにより良好にコントロールされている鎌状赤血球症の14歳女児 (2017)
  • Author(s): 川口 裕之, 小倉 友美, 關中 佳奈子, 關中 悠仁, 野々山 恵章
  • Organizer: 第120回日本小児科学会学術集会
• [Presentation] 急性巣状細菌性腎炎の治療中に川崎病および血球貪食症候群を発症した1例 (2017)
  • Author(s): 西村 直人, 中川 紀子, 野村 智章, 藤田 基資, 釜江 智佳子, 金井 貴志, 滝沢 真理, 川口 裕之, 黒木 康富
  • Organizer: 第120回日本小児科学会学術集会
• [Presentation] 溶連菌感染後糸球体腎炎を合併した免疫性血小板減少性紫斑病の6歳男児例 (2017)
  • Author(s): 釜江 智佳子, 浅野 貴子, 山本 かずな, 野村 智章, 金井 貴志, 中川 紀子, 滝沢 真理, 川口 裕之, 野々山 恵章, 黒木 康富
  • Organizer: 第52回小児腎臓病学会
• [Presentation] 間欠的チアノーゼを伴う鉄剤不応性貧血の13歳女児 (2017)
  • Author(s): 川口裕之、谷口留美、古谷憲孝、高見澤勝
  • Organizer: 第6回日本血液学会 関東甲信越地方会
  • Place of Presentation: 東京
• [Presentation] 角化嚢胞性歯原性腫瘍を合併したB前駆細胞型急性リンパ性白血病の一例 (2016)
  • Author(s): 渡邊敦、杣津晋平、大城浩子、赤羽弘資、合井久美子、犬飼岳史、藤井克則、宮下俊之、杉田完爾
  • Organizer: 第58回日本小児血液・がん学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-15
• [Presentation] Antitumorigenic effects of azacitidine via up-regulation of CDH1 transcription in childhood AML (2016)
  • Author(s): 関中佳奈子、関中悠仁、小倉友美、本田護、武純也、野々山恵章、川口裕之
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Entire PTCH1 deletions detected in 9 families with nevoid basal cell carcinoma syndrome (2016)
  • Author(s): 高山吉永、長尾一右、藤井克則、宮下俊之
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] 小児aCML症例の分子生物学的検討 (2016)
  • Author(s): 關中悠仁 、關中-三井 佳奈子 、川口 裕之
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Gorlin症候群における脳形態解析－ヘッジホッグシグナルのヒト脳への影響－ (2016)
  • Author(s): 塩浜直、藤井克則、宮下俊之、内川英紀、水落弘美、池原甫、福原知之、下条直樹
  • Organizer: 第58回日本小児神経学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-06-03
• [Presentation] Splenic sequestrationによる急激な貧血の進行が疑われた鎌状赤血球症とβサラセミアの複合ヘテロ変異の一例 (2016)
  • Author(s): 本田護、小倉友美、關中悠仁、關中佳奈子、川口裕之、野々山恵章
  • Organizer: 第119回日本小児科学会
  • Place of Presentation: 札幌
  • Year and Date: 2016-05-13
• [Presentation] デジタルPCRによるMRD解析を行った急性骨髄性白血病の２例 (2016)
  • Author(s): 小倉友美、川口裕之、関中佳奈子、本田護、関中悠仁、磯部清孝、小山千草、荒川ゆうき、康勝好、野々山恵章
  • Organizer: 第119回日本小児科学会
  • Place of Presentation: 札幌
  • Year and Date: 2016-05-13
• [Presentation] 多発する手掌の小陥凹を契機に発見されたGorlin症候群の１例 (2016)
  • Author(s): 大橋洋之、武内聡美、北澤智子、村上富美子、宮下俊之
  • Organizer: 第870回日本皮膚科学会東京地方会
  • Place of Presentation: 東京
• [Presentation] CRISPR/Cas9システムを用いた2点同時切断による目的ゲノム領域除去細胞株の作製 (2015)
  • Author(s): 加藤千勢、長尾和右、初瀬洋美、高山吉永、亀山孝三、宮下俊之
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸市
  • Year and Date: 2015-12-01
• [Presentation] 次世代シークエンサーを用いた血小板異常症の迅速遺伝子診断法の確立 (2015)
  • Author(s): 小倉友美、川口裕之、關中悠仁、關中佳奈子、野々山恵章
  • Organizer: 第57回小児血液・がん学会
  • Place of Presentation: 甲府市
  • Year and Date: 2015-11-27
• [Presentation] Intragenic amplification of PAX5 in oediatric B-cell precursor acute lymphoblastic leukemia (2015)
  • Author(s): Yano N, Imamura T, Ohki K, Asai D, Deguchi T, Hashii T, Takahashi H, Kanai R, Yajima S, Kosaka Y, Kawaguchi H, Kikuta A, Sato A
  • Organizer: 第57回小児血液・がん学会
  • Place of Presentation: 甲府市
  • Year and Date: 2015-11-27
• [Presentation] デジタル PCR による MRD 解析を行った CBFA2T3-GLIS2/DHH-THEBL1 陽性 AMkL の 1 例 (2015)
  • Author(s): 關中佳奈子、原勇介、川口裕之、關中悠仁、小倉友美、小山千草、荒川ゆうき、康勝好、林泰秀、野々山恵章
  • Organizer: 第57回小児血液・がん学会
  • Place of Presentation: 甲府市
  • Year and Date: 2015-11-27
• [Presentation] 経過中にヘモグロビンF上昇を認めた ML-DS の2症例 (2015)
  • Author(s): 關中悠仁 、川口 裕之、本田護、關中-三井 佳奈子、小倉 友美、宮内潤、野々山 恵章
  • Organizer: 第57回小児血液・がん学会
  • Place of Presentation: 甲府市
  • Year and Date: 2015-11-27
• [Presentation] NIPA (Nuclear interating partner gene with ALK) の転写抑制による小児固形腫瘍細胞株の増殖態度の変化の検討 (2015)
  • Author(s): 川口 裕之、小倉 友美、關中 悠仁、三井-關中 佳奈子、野々山 恵章、宮内 潤
  • Organizer: 第57回小児血液・がん学会
  • Place of Presentation: 甲府市
  • Year and Date: 2015-11-27
• [Presentation] Establishment of the cell lines with a large genomic deletion by CRISPR/Cas9 system (2015)
  • Author(s): 長尾和右、高山吉永、宮下俊之
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-08
• [Presentation] CRISPR/Cas9システムを用いた広域欠損ゲノムを有する細胞株の作製 (2015)
  • Author(s): 加藤千勢、高山吉永、亀山孝三、初瀬洋美、長尾和右、宮下俊之
  • Organizer: 第28回北里大学バイオサイエンスフォーラム
  • Place of Presentation: 相模原市
  • Year and Date: 2015-08-06
• [Presentation] マウス初期杯におけるOct4の機能解析 (2015)
  • Author(s): 三谷温、宮下俊之、阿久津英憲
  • Organizer: 第28回北里大学バイオサイエンスフォーラム
  • Place of Presentation: 相模原市
  • Year and Date: 2015-08-06
• [Presentation] 組織球肉腫と微小浸潤性扁平上皮癌の成分からなる稀な食道癌肉腫の1例 (2015)
  • Author(s): 宮内 潤
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-30
• [Book] 小児腫瘍組織カラーアトラス（第７巻）：胚細胞腫瘍およびその他の臓器特異的希少腫瘍 (2017)
  • Author(s): 井上 健、大喜多肇、小田義直、中澤温子、中山雅弘、浜崎 豊、平戸純子、藤本純一郎、北條 洋、堀江 弘、宮内 潤、森川征彦、横山繁昭
  • Total Pages: 114
  • Publisher: 金原出版
  • ISBN: 9784307170710