記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AMeD syndrome is characterized by aplastic anemia, mental retardation, short stature, and microcephaly and is caused by digenic mutations in the aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 5 (ADH5) genes. We have successfully performed hematopoietic stem cell transplantation in two patients with AMeD syndrome and isochromosome 1q. AMeD syndrome with myelodysplastic syndrome or acute myeloblastic leukemia generally has a poor prognosis; however, early diagnosis may improve treatment response. Although the gain of 1q has been considered as a form of early clonal evolution in Fanconi anemia, it may be an equally important finding observed in AMeD syndrome.

DOI： 10.1016/j.lrr.2024.100476

PubMed

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

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記述言語：英語   出版者・発行元：(一社)日本血液学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：The Japan Epilepsy Society  

DOI： 10.3805/eands.14.51

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記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

結節性硬化症は全身の過誤腫を特徴とする疾患である。頭部の腫瘍性病変は側脳室壁に好発するsubependymal giant cell astrocytoma(SEGA)の頻度が高いが、まれに膠芽腫の発症も報告されている。症例は9歳男児。生後5ヵ月時の点頭てんかんの発症を契機として結節性硬化症と診断された。頭部CTで左前頭葉に石灰化を伴う皮質下結節を認めていた。誘因なく突然嘔吐するエピソードを2週間で数回認めたため、頭部CTを施行したところ左前頭葉に出血を伴う腫瘍性病変を認めた。この数時間後より頻回の嘔吐、意識障害を認めたため、頭部CTを再検したところ腫瘍内出血が急激に増悪し、頭蓋内圧亢進状態であった。緊急で腫瘍摘出術が施行され、病理検査結果から膠芽腫と診断された。SEGAが良性腫瘍であるのに対し、膠芽腫は悪性度が高く、急速に増大し、一般的に予後は不良である。結節性硬化症の頭部病変ではSEGA以外の腫瘍の発症も念頭に入れ、有症状のときには速やかな画像評価が必要である。また知的障害や自閉スペクトラム症を高率に合併し、神経学的症状を把握しづらい状況も考えられるため注意する必要がある。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01232&link_issn=&doc_id=20210113300009&doc_link_id=%2Fcl1nohat%2F2021%2F005301%2F012%2F0049-0052%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcl1nohat%2F2021%2F005301%2F012%2F0049-0052%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Pediatric patients in Japan are diagnosed with IgAN at an early stage of the disease through annual urinary examinations. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) have various roles, including proinflammatory effects, and modulation of several kidney diseases; however, no reports have described their roles in pediatric IgAN. In this study, we performed pathological and immunohistochemical analyses of samples from 14 pediatric IgAN patients. Additionally, gene expression arrays of glomeruli by laser-captured microdissection were performed in hemi-nephrectomized high serum IgA (HIGA) mice, a model of IgA nephropathy, to determine the role of Fn14. Glomeruli with intense Fn14 deposition were observed in 80% of mild IgAN cases; however, most severe cases showed glomeruli with little or no Fn14 deposition. Fn14 deposition was not observed in obvious mesangial proliferation or the crescent region of glomeruli, but was detected strongly in the glomerular tuft, with an intact appearance. In HIGA mice, Fn14 deposition was observed mildly beginning at 11 weeks of age, and stronger Fn14 deposition was detected at 14 weeks of age. Expression array analysis indicated that Fn14 expression was higher in HIGA mice at 6 weeks of age, increased slightly at 11 weeks, and then decreased at 26 weeks when compared with controls at equivalent ages. These findings suggest that Fn14 signaling affects early lesions but not advanced lesions in patients with IgAN. Further study of the TWEAK/Fn14 pathway will contribute to our understanding of the progression of IgAN.

DOI： 10.1371/journal.pone.0258090

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記述言語：英語  

The most common organisms isolated from pediatric catheter-related bloodstream infections (CRBSIs) are Gram-positive cocci, such as coagulase-negative staphylococci and Staphylococcus aureus. There are few formal reports of Brevibacterium casei infection and even fewer reports of CRBSI due to this Gram-positive rod. Here we report the first case of CRBSI due to B. casei in an 8-year-old girl with acute myeloid leukemia in Japan. The isolate exhibited decreased susceptibility to ß-lactam antibiotics. Antimicrobial therapy with meropenem and vancomycin, in addition to the removal of central venous catheter line, consequently led to a significant clinical improvement of the patient's symptoms. A literature review found available clinical courses in 16 cases (4 pediatric cases including our case) of B. casei infection. Our case and those in literature suggested that B. casei infection often occurs in patients with indwelling central venous catheters; the literature review further suggested that removal of central venous catheters is required in most cases. Special attention should be paid to the detection of opportunistic infections due to Brevibacterium spp. in immunocompromized children who are using a central venous catheter.

DOI： 10.1155/2021/6691569

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background. Staphylococcus lugdunensis is one of the clinically important coagulase-negative staphylococci. The purpose of this study was to elucidate the microbiological features of S. lugdunensis in hospitalized children. Methods. From January 2012 to December 2019, all isolates were retrospectively screened for S. lugdunensis. Results. Twenty-five children were eligible for study. Nineteen and six children were classified into a critical care unit group (Group A) and a general medical ward group (Group B), respectively. The prevalence of methicillin-resistant S. lugdunensis was significantly higher in Group A than in Group B (68.4% vs 0%; P < .01). Eleven children (44%) had S. lugdunensis infections, while the remaining children were colonized. Six of the 11 infected children (55%) had healthcare-associated infections. Moreover, 3 isolates exhibited the methicillin resistance. Conclusions. The bacteriological characteristics of S. lugdunensis differ depending on patient background. Selection of antibiotic treatment should in part rely on patient background data.

DOI： 10.1177/2333794X211044796

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記述言語：日本語   出版者・発行元：(同)クリニコ出版  

AYA世代とは、adolescent and young adult(思春期・若年成人)世代の略称であり、概ね15〜39歳と定義されている。この世代に発生する"がん"の特徴として、小児期とは異なり、成人でみられる"がん"の発症が認められるが、小児期と同様に、白血病や悪性リンパ腫も高頻度に認められる。小児期の白血病の治療成績は著明に改善しているが、AYA世代の白血病の治療成績は未だ満足できるものではない。また高齢者に比較すると生存率は高いが、晩期合併症や二次がんの発症が認められ、治療後のQOL(quality of life)は必ずしも高くないことに注目する必要がある。また、AYA世代のがん患者は年齢依存的な心理・社会的な問題が複雑であり、これらの問題点を一つひとつ解決していくことが重要である。(著者抄録)

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語  

Brain abscesses, infections within the brain parenchyma, can arise as complications of various conditions including infections, trauma, and surgery. However, brain abscesses due to polymicrobial organisms have rarely been reported in children. We herein report a case of a 9-year-old girl with unresolved congenital cyanotic heart disease (CCHD) presenting with right hemiplegia who was diagnosed with brain abscess caused by Streptococcus intermedius, Parvimonas micra, and Fusobacterium nucleatum after oropharyngeal injury. She was treated with intravenous antimicrobial therapy, drainage under craniotomy, and antiedema therapy with glycerol and goreisan, which led to the improvement of right hemiplegia to baseline; she was discharged following eight weeks of intravenous antimicrobial therapy. The clinical diagnosis of the brain abscess was difficult due to the nonspecific presentation, highlighting the importance of cranial imaging without haste in patients at increased risk for brain abscesses such as those with CCHD, presenting with fever in the absence of localizing symptoms or fever, accompanied with abnormal neurological findings.

DOI： 10.1155/2020/8304302

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/gcc.22734

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記述言語：日本語   出版者・発行元：金原出版(株)  

＜文献概要＞白血病は小児で最も多い悪性腫瘍であり,その治療成績は著明に改善し,多くの小児患者で治癒が得られている.治療成績の向上に寄与した要因の一つが染色体・遺伝子異常によるリスク層別化である.白血病の有する染色体異常・遺伝子異常はしばしば病型特異的であり,正確な診断・病型分類のみならず,治療方針の選択や予後を推測するうえで重要な情報でもある.近年の核酸解析技術の進歩により,白血病の有する遺伝子異常に関する情報は飛躍的に増加した.それらの意義づけと治療に有用な情報の選択が今後の課題である.白血病診療においては可能な限り分子遺伝学的な異常の有無を検索し,遺伝子異常に基づくリスク評価と治療法の選択が必須である.

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00639&link_issn=&doc_id=20190618110003&doc_link_id=10.18888%2Fsh.0000000943&url=https%3A%2F%2Fdoi.org%2F10.18888%2Fsh.0000000943&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

MLL遺伝子再構成陽性の乳児急性リンパ性白血病(MLL-r ALL)は予後不良の疾患である。日本では1996年より乳児ALLをMLL遺伝子再構成の有無で層別化し、MLL-r群に対しては化学療法と造血幹細胞移植(HSCT)を併用する治療法を実施した。これまでMLL96、MLL98、MLL03、MLL10研究を経て近くMLL16治療研究が開始される予定であるが、ほとんど生存が得られなかった乳児MLL-r ALLの無イベント生存率は約50%まで改善した。乳児白血病の発症機序については胎生期のMLL再構成が1st hitとなるが、その後に起こる2nd hitについては不明である。我々はMLL-r乳児ALLは、let-7b-MGA2-p16系の破綻により幹細胞の分化が抑制され白血病化が誘導される可能性を明らかにした。このような病態解析により乳児ALLに対して脱メチル化剤などの分子標的薬が有効である可能性がある。一方乳児白血病の発症は1 hitのみで充分だという論文が報告されたが、我々はマウスを用いた実験で乳児白血病発症には何らかの2nd hitが必要であることを明らかにした。今後さらに解析を進めて乳児白血病の発症機序を明らかにし、新たな治療法を開発していく必要がある。(著者抄録)

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DOI： 10.1155/2019/7890673

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記述言語：日本語   出版者・発行元：愛媛医学会  

J-GLOBAL

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DOI： 10.1080/08880018.2018.1539148

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DOI： 10.1080/08880018.2018.1522402

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DOI： 10.1080/08880018.2018.1459984

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley-Liss Inc.  

22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life-threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D-2- and L-2-hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed.

DOI： 10.1002/ajmg.a.38578

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Gaucher disease is a lysosomal storage disease caused by deficiency of glucocerebrosidase and accumulation of glucocerebroside. Three major sub-types have been described, type 2 is an acute neurological form that exhibits serious general symptoms and poor prognosis, compared with the other types. This case was a girl diagnosed with type 2 Gaucher disease at 12 months of age who presented with poor weight gain from infancy, stridor, hypertonia, hepatosplenomegaly, trismus and an eye movement disorder. Enzyme replacement therapy (ERT) was administered, but she had frequent myoclonus and developmental regression. She needed artificial ventilation because of respiratory failure. She died at 11 years of age. An autopsy demonstrated infiltrating CD68-positive large cells containing abundant lipids in alveoli, while in the liver, kidney and bone marrow CD68-positive cells were small and round. In the bone marrow, myelodysplastic changes were present without Gaucher cells. The infiltration of Gaucher cells in alveoli was marked, suggesting that ERT was relatively ineffective in pulmonary involvement, particularly intra-alveolar. Additional treatments are necessary to improve the neurological and pulmonary prognosis of type 2 Gaucher disease. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bcmd.2016.11.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

We report the case of a 10-year-old female with acute myeloid leukemia (AML) FAB M0 carrying a novel t(11;19)(q23;p13.1) MLL-ELL variant, in which intron 8 of MLL is fused to exon 6 of ELL. Complete remission, judged by morphology and cytogenetic analysis, was achieved after the conventional chemotherapy. Eight months after completion of therapy, the level of WT-1 in peripheral blood and the number of cells with the MLL-ELL fusion transcript resurged. However, the patient remained overtly healthy and the morphology in the bone-marrow smear was innocuous, with no sign of relapse or secondary leukemia. Without any evidence of relapse, the patient has been closely observed without any therapeutic intervention. For approximately 2 years after the completion of therapy, despite clonal proliferation of pre-leukemic cells with an MLL-ELL fusion gene, she has maintained complete remission. In this case, the rare variant form of MLL-ELL fusion that has been identified may be related to diminished leukemogenic capacity, resulting in the persistence of pre-leukemic status; an additional genetic abnormality may thus be necessary for full transformation of pre-leukemic cells.

DOI： 10.1007/s12185-017-2289-y

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Springer Singapore  

Hematopoietic stem cells (HSCs), which are responsible for producing all blood cell types, first appear in the early stage of embryonic development and transit through several different tissues, including the yolk sac, aorta-gonad-mesonephros (AGM) region, placenta, and fetal liver, before colonizing in the bone marrow where they reside throughout the individual's life. HSCs, characterized by the ability to self-renew and generate all types of blood cells, are supported by their specific environment called niches and depend on many developmental signaling pathways, molecules, and cytokines for their generation, maintenance, and expansion. Any disruption in this well-balanced system may cause aberrant HSC production, leading to malignant hematopoiesis. Leukemic stem cells (LSCs), originally identified using xenograft models of acute myeloid leukemia (AML), are a distinct cell population that can initiate leukemia in immunodeficient mice. LSCs are thought to emerge from HSCs or hematopoietic progenitors after obtaining multiple genetic changes that provide aberrant growth advantage and self-renewal ability. The emergence of LSCs is a multi-step event, including genetic diversification and clonal selection, resulting in genetic heterogeneity among leukemic cells. LSCs generally exist in the immature CD34+CD38- leukemic population in most cases of AML and share some features with normal HSCs. However, recent studies have shown that in acute lymphoblastic leukemia (ALL), LSCs exist in B-lineage-committed progenitors expressing CD19. In contrast to that in AML, in which LSCs generate leukemic cells in a hierarchical order with LSCs at the top, leukemia propagation in ALL is better explained by a stochastic model.

DOI： 10.1007/978-981-10-3886-0_1

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background: Recently, a student died of idiopathic ventricular fibrillation in a school where an automated external defibrillator (AED) had been installed. The tragedy could not be prevented because the only AED in the school was installed in the teachers' office, far from the school ground where the accident took place. This prompted establishment of a multiple AED system in schools. The aim of this study was to analyze the efficacy of the multiple AED system to prevent sudden death in school-aged children.
Methods: Assumed accident sites consisted of the school ground, gymnasium, Judo and Kendo hall, swimming pool, and classrooms on the first and the fourth floor. Multiple AED were installed in the teachers' office, gymnasium, some classrooms, and also provided as a portable AED in a rucksack. The time from the accident site to the teachers' office for single AED, and from the accident site to the nearest AED for multiple AED, was calculated.
Results: The AED retrieval time was significantly shorter in 55 elementary schools and in 29 junior high schools when multiple AED were installed compared with single AED. Except for the classroom on the fourth floor, the number of people who took &gt;120 s to bring the AED to the accident site was lower when multiple AED were installed compared with the single AED.
Conclusion: Multiple AED provided in appropriate sites can reduce the time to reach the casualty and hence prevent sudden death in school-aged children.

DOI： 10.1111/ped.13143

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long-term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MU) fusion, the microRNA let-7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A-AFF1 (MLL-AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin-dependent kinase inhibitor p16(INK4A). The HMGA2 inhibitor nctropsin, when combined with demethylating agent 5-azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A-AFF1-expressing cell lines. This effect was more apparent compared to treatment with 5-azacytidine alone. These results indicate that the MIRLET7B-HMGA2-CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A-AEF1.

DOI： 10.1111/bjh.13763

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society of Hematology  

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplan-tation model. In MLL-AF4 patients, CD34+CD38+CD19+ and CD34-CD19+ cells initiated leukemia, and in MLL-AF9 patients, CD34-CD19+ cells were LICs. In MLL-ENL patients, either CD34+ or CD34- cells were LICs, depending on the pattern of CD34 expression. In contrast, inpatients with these MLL translocations, CD34+CD38-CD19-CD33- cellswere enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulationc apacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34+CD38-CD19-CD33-cells repopulated recipient bone marrow and spleen with B cells, showing broad poly-clonal IGH rearrangement and recipient thymus with CD4+ single positive(SP), CD8+ SP, and CD4+CD8+ double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34+CD38+ and CD34- LICs but not in CD34+CD38-CD19-CD33- HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lym-phoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.

DOI： 10.1182/blood-2014-03-563304

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Juvenile myelomonocytic leukemia (JMML) is a clonal disease arising from abnormal hematopoietic stem cells, although the involvement of lymphoid lineage differs among reported cases. Here, we present a case of JMML with a KRAS G13D mutation. The mutation was detected in various hematopoietic lineages, including T and B lymphocytes and also in lineage(-) CD34(+)CD38(-) hematopoietic stem cells, showing a different percentage of affected cells in each lineage. Single cell-based analysis of hematopoietic cells revealed the loss of wild-type KRAS in a significant proportion of G13D-harboring cells. The percentage of loss of heterozygosity (LOH)/non-LOH cells showed lineage-dependent skewing in hematopoietic cells. The loss of the wild-type KRAS allele may be a common secondary genetic change in KRAS-related JMML and may affect the differentiation behavior of early JMML progenitors.

DOI： 10.1111/ejh.12355

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC HEMATOLOGY  

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.

DOI： 10.1182/blood-2014-03-563304

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記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

白血病発症機構の理解は白血病幹細胞の概念により大きく進展した。白血病幹細胞は全ての白血病細胞が派生しうる幹細胞としての能力を有する一群の細胞で，免疫不全マウスに白血病を再現できる細胞群(leukemia-initiating cell)として表現される。急性骨髄性白血病(AML)では白血病幹細胞は白血病細胞集団内にごく少数存在し，CD34&lt;sup&gt;+&lt;/sup&gt;CD38&lt;sup&gt;-&lt;/sup&gt;という正常造血幹細胞に類似した細胞形質を示す。一方小児の急性リンパ性白血病(ALL)を用いた研究ではCD19陽性のより分化した細胞群が白血病幹細胞としての活性を有しており，病型により白血病幹細胞にも多様性が認められることが報告されている。白血病幹細胞を頂点とした階層性(hierarchy)を形成するAMLとは対照的に，ALLではCD19陽性の白血病幹細胞が，自己複製能を同様に有する下流の白血病幹細胞を形成すると考えられ，その進展様式は確率論モデル(stochastic model)に従うと考えられている。白血病の再発予防や予後改善のために，白血病幹細胞に関する研究の今後の進展が待たれる。

DOI： 10.11406/rinketsu.56.1871

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/hgv.2015.4

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記述言語：日本語   出版者・発行元：科学評論社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a subtype of acute myeloid leukemia, affecting mainly the elderly. It is thought to be derived from plasmacytoid dendritic cell precursors, which frequently present as cutaneous lesions. We have made a detailed analysis of an infant with BPDCN, who manifested with hemophagocytic lymphohistiocytosis. The peripheral blood leukocytes revealed the t(2;17;8)(p23;q23;p23) translocation and a CLTC-ALK fusion gene, which have never been reported in BPDCN or in any myeloid malignancies thus far. Neonatal blood spots on the patient's Guthrie card were analyzed for the presence of the CLTC-ALK fusion gene, identifying the in utero origin of the leukemic cell. Although the leukemic cells were positive for CD4, CD56, CD123, and CD303, indicating a plasmacytoid dendritic cell phenotype, detailed analysis of the lineage distribution of CLTC-ALK revealed that part of monocytes, neutrophils, and T cells possessed the fusion gene and were involved in the leukemic clone. These results indicated that leukemic cells with CLTC-ALK originated in a multipotent hematopoietic progenitor in utero. This is the first report of the CLTC-ALK fusion gene being associated with a myeloid malignancy, which may give us an important clue to the origin of this rare neoplasm. (c) 2013 Wiley Periodicals, Inc.

DOI： 10.1002/gcc.22119

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記述言語：日本語   出版者・発行元：(株)中外医学社  

1歳未満の乳児期に発症する白血病は,他の小児白血病と比し白血球数の著増,肝脾腫や中枢神経浸潤などの髄外浸潤を高率に合併するなど,特徴的な臨床像を呈する.乳児白血病ではMLL遺伝子再構成が高率にみられ,その有無が予後を規定する.特にMLL遺伝子再構成陽性の乳児急性リンパ性白血病は極めて難治であり,分子標的療法など,新たな治療法の開発が強く望まれる.近年の網羅的な遺伝子プロファイリングは,造血細胞の白血病化と生存に必要な要因を抽出するにあたり有効な方法であり,MLL遺伝子再構成陽性例を含む乳児白血病でもその病態が次第に解明されつつある.遺伝子発現プロファイリングの臨床応用により,白血病の病態の解明,および白血病細胞の性格に基づいた精度の高いリスク評価により,個々の症例に応じた適確な治療法への道が開きつつある.(著者抄録)

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：(一社)日本小児血液・がん学会  

同種造血幹細胞移植後にドナー由来の悪性腫瘍を発症することはまれである。症例は6歳女児。生後30生日で急性リンパ性白血病と診断し、生後4ヵ月時に第一寛解期で非血縁者間臍帯血移植を施行した。ドナーは男児で、human leukocyte antigen(HLA)はDNA型で4/6一致であった。移植後12ヵ月目に骨髄再発したため、第二寛解期に非血縁者間骨髄移植を施行した。ドナーは男性でHLAはDNA型で6/6一致であった。2回目の移植から47ヵ月後に、定期検査で末梢血にアウエル小体を有する芽球を認め、その4ヵ月後に骨髄異形成症候群(MDS)/急性骨髄性白血病(AML)と確定診断した。末梢血の芽球・Tリンパ球のHLA検査で骨髄ドナー由来のMDS/AMLと判明した。MDS/AMLに対して非血縁者間骨髄移植を行い、現時点で寛解を維持している。本症例では、化学療法と移植、および免疫抑制剤の長期使用による骨髄環境の変化がMDS/AML発症の要因になった可能性が考えられた。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

MicroRNAs (miRNAs) regulate cell proliferation and differentiation by controlling the expression of proteins involved in many signaling pathways. Recent studies have shown that dysregulation of miRNA expression is associated with increased tumorigenicity and a poor prognosis in several types of cancers. The miRNA let-7b is one of the severely downregulated miRNAs in mixed-lineage leukemia (MLL)-rearranged acute lymphoblastic leukemia (ALL) patients. In vitro transfection of leukemogenic MLL fusion genes into human embryonic kidney-293 cells suppressed let-7b expression. In leukemic cells with an MLL fusion gene, the regulatory region for let-7b expression was hypermethylated, and its expression was partially recovered after culturing the cells with the demethylating agent 5-azacitidine. These results suggest that loss of let-7b expression may be one of the consequences of oncogenic MLL fusion proteins, and contributes to leukemogenesis possibly through the upregulation of let-7b-regulated target genes with leukemogenic potential in hematopoietic cells. The enforced expression of let-7b in ALL cell lines with an MLL fusion gene inhibited their growth, indicating the possible use of let-7b as a new therapeutic tool for refractory infant ALL with an MLL fusion gene. © 2013 Macmillan Publishers Limited All rights reserved.

DOI： 10.1038/leu.2012.242

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記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

DOI： 10.11406/rinketsu.52.686

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

HDR syndrome is an autosomal dominant disorder characterized by hypoparathyroidism, sensorineural deafness, and renal anomaly caused by mutation of the GATA3 gene located at chromosome 10p15. We report the case of a neonate with HDR syndrome and a novel GATA3 mutation. We performed genetic and functional analysis of GATA3 in this patient and identified a novel heterozygous 1516G &gt; C missense mutation in exon 5, resulting in a cysteine-to-serine substitution at codon 321 (Cys321Ser). Mutated and wild-type GATA3 proteins were expressed at a similar level in vitro, indicating that the mutated GATA3 protein was stable. Luciferase assay revealed that the Cys321Ser-mutated GATA3 lacked transactivation activity due to loss of DNA-binding activity as confirmed by gel shift assay. Moreover, mutated GATA3 exerted a dominant-negative effect over the transactivation activity of wild-type GATA3. These findings indicate that not only haploinsufficiency of GATA3 but also the dominant-negative effect of Cys321Ser-mutated GATA3 might have been responsible for the HDR syndrome phenotype of our patient.

DOI： 10.1007/s00109-010-0702-6

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記述言語：日本語   出版者・発行元：(株)中外医学社  

エピジェネティックな変化であるDNAメチル化は,同一の遺伝情報(DNA)から組織特異的な発現を獲得するための遺伝子発現制御機構として,組織発生や細胞分化,増殖のコントロールに重要な役割を果たしている.白血病を含む悪性腫瘍では,DNAメチル化異常による癌抑制遺伝子の発現消失は,染色体異常や遺伝子変異と並び,腫瘍の進展に関与する重要な因子である.近年のゲノムワイドな解析により,白血病では癌抑制遺伝子のみではなく,様々な機能を有する数多くの遺伝子が異常なDNAメチル化を介して発現異常をきたしていることが明らかになってきた.メチル化される遺伝子群は,その病型により特徴的なパターンをとる.またメチル化が予後と相関する遺伝子も同定され,予後予測因子としてのDNAメチル化異常も注目されている.DNAメチル化に基づく遺伝子の発現異常は,脱メチル化剤によって解除される可逆的な変化であり,治療標的としての重要性も高い.(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

The ETS variant gene 6 (ETV6) gene is located at 12p13, and is frequently involved in translocations in various human neoplasms, resulting in the expression of fusion proteins consisting of the amino-terminal part of ETV6 and unrelated transcription factors or protein tyrosine kinases. Leukemia with t(1;12)(q21;p13) was previously described in a 5-year-old boy with acute myeloblastic leukemia (AML-M2) who exhibited a novel ETV6-aryl hydrocarbon receptor nuclear translocator (ARNT) fusion protein. We herein report the case of a 2-year-old boy with T-cell lymphoblastic leukemia (T-ALL) harboring t(1;12)(q21;p13). Fluorescence in situ hybridization (FISH) with a ETV6 dual-color DNA probe revealed that the split signals of the ETV6 gene in 96.7% of bone marrow cells, indicating rearrangement of the ETV6 gene. Therefore, we performed a FISH analysis with bacterial artificial chromosome (BAC) probes containing the ARNT, BCL9, and MLLTI1 genes located at 1q21, and these results indicated that the ARNT gene might be involved in the t(1;12)(q21;p13). Reverse transcriptase-polymerase chain reaction analysis disclosed the existence of a ETV6-ARNT fusion gene. To our knowledge, the current report is novel in its report of the ETV6-ARNT fusion in childhood T-ALL. The ETV6 ARNT fusion is associated not only with AML but also with T-ALL. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cancergencyto.2010.07.121

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：金原出版  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

TEL/ETV6 located at chromosome 12p13 encodes a member of the E26 transformation-specific family of transcription factors. TEL is known to be rearranged in a variety of leukemias and solid tumors resulting in the formation of oncogenic chimeric protein. Tel is essential for maintaining hematopoietic stem cells in the bone marrow. To understand the role of TEL in erythropoiesis, we generated transgenic mice expressing human TEL under the control of Gata1 promoter that is activated during the course of the erythroid-lineage differentiation (GATA1-TEL transgenic mice). Although GATA1-TEL transgenic mice appeared healthy up to 18 months of age, the level of hemoglobin was higher in transgenic mice compared to non-transgenic littermates. In addition, CD71(+)/TER119(+) and c-kit(+)/CD41(+) populations proliferated with a higher frequency in transgenic mice when bone marrow cells were cultured in the presence of erythropoietin and thrombopoietin, respectively. In transgenic mice, enhanced expression of Alas-e and beta-major globin genes was observed in erythroid-committed cells. When embryonic stem cells expressing human TEL under the same Gata1 promoter were differentiated into hematopoietic cells, immature erythroid precursor increased better compared to controls as judged from the numbers of burst-forming unit of erythrocytes. Our findings suggest some roles of TEL in expanding erythroid precursors and accumulating hemoglobin. (Cancer Sci 2009; 100: 689-697)

DOI： 10.1111/j.1349-7006.2009.01097.x

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記述言語：英語   出版者・発行元：SPRINGER TOKYO  

DOI： 10.1007/s12185-009-0267-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC HEMATOLOGY  

Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis in DS-ALL, we undertook sequencing of candidate genes, including FLT3, RAS, PTPN11, BRAF, and JAK2. Sequencing of the JAK2 pseudokinase domain identified a specific, acquired mutation, JAK2R683, in 12 (28%) of 42 DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells showed growth factor independence and constitutive activation of the JAK/STAT signaling pathway. High-resolution SNP array analysis of 9 DS-ALL cases identified additional submicroscopic deletions in key genes, including ETV6, CDKN2A, and PAX5. These results infer a complex molecular pathogenesis for DS-ALL leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events. (Blood. 2009; 113: 646-648)

DOI： 10.1182/blood-2008-08-170928

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

The treatment outcome for infant acute lymphoblastic leukemia (ALL) with positive MLL gene rearrangements remains poor. We analyzed whether additional chromosomal abnormalities (ACA) other than 11q23 translocation could affect the disease behavior and its prognosis.
Eighteen of seventy-four patients with infant acute lymphoblastic leukemia showed ACA, including three-way translocations in four, other novel translocations in four, and complex structural chromosomal changes in four. Only age less than 6 months and positive central nervous system leukemia were significant prognostic factors by multivariate analysis. However, overall survival rates were worse in patients with ACA compared to those with non-ACA. Genetic alterations induced by additional chromosomal changes may be associated with disease progression and poorer overall survival rates in infants with MLL-rearranged ALL. Crown Copyright (c) 2008 Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2009.03.018

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その他リンク： http://orcid.org/0000-0003-1520-7007

記述言語：日本語   出版者・発行元：(一社)日本血液学会-東京事務局  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC HEMATOLOGY  

NOTCH1 mutations are common in T-lineage acute lymphoblastic leukemia (TALL). Twin studies and retrospective screening of neonatal blood spots provide evidence that fusion genes and other chromosomal abnormalities associated with pediatric leukemias can originate prenatally. Whether this is also the case for NOTCH1 mutations is unknown. Eleven cases of T-ALL were screened for NOTCH1 mutations and 4 (36%) had mutations in either the heterodimerization (HD) or proline glutamic acid/serine/threonine (PEST) domains. Of these 4, 3 could be amplified by mutation-specific polymerase chain reaction primers. In one of these 3, with the highest sensitivity, NOTCH1 mutation was detected in neonatal blood spots. In this patient, the blood spot was negative for SIL-TAL1 fusion, present concomitant with NOTCH1 mutation, in the diagnostic sample. We conclude that NOTCH1 can be an early or initiating event in T-ALL arising prenatally, to be complemented by a postnatal SIL-TAL1 fusion.

DOI： 10.1182/blood-2007-02-074690

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記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/sj.leu.2404397

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記述言語：英語   出版者・発行元：WILEY-LISS  

PILL fusion genes are a predominant feature of acute leukemias in infants and in secondary acute myeloid leukemia (AML) associated with prior chemotherapy with topo-II poisons. The former is considered to possibly arise in utero via transplacental chemical exposure. A striking feature of these leukemias is their malignancy and remarkably brief latencies implying the rapid acquisition of any necessary additional mutations. We have suggested that these coupled features might be explained if MLL fusion gene encoded proteins rendered cells more vulnerable to further DNA damage and mutation in the presence of chronic exposure to the agent(s) that induced the MLL fusion itself. We have tested this idea by exploiting a hormone regulated MLL-ENL (MLLTI) activation system and show that MLL-ENL function in normal murine progenitor cells substantially increases the incidence of chromosomal abnormalities in proliferating cells that survive exposure to etoposide VP-16. This phenotype is associated with an altered pattern of cell cycle arrest and/or apoptosis. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/gcc.20338

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記述言語：日本語   出版者・発行元：(株)医薬ジャーナル社  

チロシンキナーゼは細胞の増殖をコントロールする細胞生存に必須のタンパク質である.近年慢性骨髄増殖疾患においてチロシンキナーゼJak2の変異が同定され,チロシンキナーゼがその発症に果たす役割が注目されている.一方,骨髄増殖性疾患ではTEL-PDGFRβのように染色体転座にともなうチロシンキナーゼ異常も認められる.転写因子TEL/ETV6(translocation Ets leukemia/Ets variant gene 6)とPDGFRβ(platelet derived growth factor receptor β)等のチロシンキナーゼとのキメラ蛋白を有する骨髄増殖性疾患は異形成をともなうことが多く,Jak2点突然変異を有する疾患群とは異なるスペクトラムの疾患群を形成する.本稿ではTEL-チロシンキナーゼキメラ蛋白を有する骨髄増殖疾患の特徴について述べる(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FERRATA STORTI FOUNDATION  

Background and Objectives. The enzyme NAD(P)H:quinone oxidoreductase (NQO1) detoxifies chemicals with quinone rings including benzene metabolites and flavonoids. Previous studies in Caucasian populations have provided evidence that a loss of function allele at nt 609 (C609T, Pro187Ser) is associated with increased risk of infant acute lymphoblastic leukemia (ALL) with MLL-AF4 fusion genes.
Design and Methods. We genotyped 103 infants (&lt;18 months) with ALL or acute myeloid leukemia (AML) in Japan and 185 controls for the frequency of allelic variation at nt 609 and 465 in NQO1 using standardized polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology.
Results. The C609T polymorphism is very common in Japan but we found no link with altered risk for infant ALL. However, a variant of another allele at nt 465 (C465T, Arg139Trp), also associated with diminished enzyme activity, was strongly associated (OR 6.36; Cl 1.84-21.90; p = 0.002) with infant ALL, especially in t(4;11)(q21;q23), MLL-AF4. No association was found between this allele and risk of infant AML with MLL gene fusions or infant ALL without MLL gene fusions. The same C465T allele has been linked recently, in an Oriental population, to sensitivity to benzene hematotoxicity.
Interpretation and Conclusions. These data endorse the notion that infant ALL with MLL fusion genes have a unique etiology possibly involving transplacental exposure to chemicals.

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記述言語：英語   出版者・発行元：CARDEN JENNINGS PUBL CO LTD  

Chromosome translocations disrupting the MLL gene are associated with various hematologic malignancies but are particularly common in infant and secondary therapy-related acute leukemias. The normal MLL-encoded protein is an essential component of a supercomplex with chromatin-modulating activity conferred by histone acetylase and methyltransferase activities, and the protein plays a key role in the developmental regulation of gene expression, including Hox gene expression. In leukemia, this function is subverted by breakage, recombination, and the formation of chimeric fusion with one of many alternative partners. Such MLL translocations result in the replacement of the C-terminal functional domains of MLL with those of a fusion partner, yielding a newly formed MLL chimeric protein with an altered function that endows hematopoietic progenitors with self-renewing and leukemogenic activity. This potent impact of the MLL chimera can be attributed to one of 2 kinds of activity of the fusion partner: direct transcriptional transactivation or dimerization/oligomerization. Key unresolved issues currently being addressed include the set of target genes for MLL fusions, the stem cell of origin for the leukemias, the role of additional secondary mutations, and the origins or etiology of the MLL gene fusions themselves. Further elaboration of the biology of MLL gene-associated leukemia should lead to novel and specific therapeutic strategies.

DOI： 10.1532/IJH97.05042

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

TEL-TRKC is a fusion gene generated by chromosomal translocation and encodes an activated tyrosine kinase. Uniquely, it is found in both solid tumors and leukemia. However, a single exon difference (in TEL) in TEL-TRKC fusions is associated with the two sets of cancer phenotypes. We expressed the two TEL-TRKC variants in vivo by using the 3' regulatory element of SCL that is selectively active in a subset of mesodermal cell lineages, including endothelial and hematopoietic stem cells and progenitors. The leukemia form of TEL-TRKC (- exon 5 of TEL) enhanced hematopoietic stem cell renewal and initiated leukemia. In contrast, the TEL-TRKC solid tumor variant (+ TEL exon 5) elicited an embryonic lethal phenotype with impairment of both angiogenesis and hematopoiesis indicative of an effect at the level of the hemangioblasts. The ability of TEL-TRKC to repress expression of Flk1, a critical regulator of early endothelial and hematopoietic cells, depended on TEL exon 5. These data indicate that related oncogenic fusion proteins similarly expressed in a hierarchy of early stem cells can have selective, cell type-specific developmental impacts.

DOI： 10.1073/pnas.0405318102

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC HEMATOLOGY  

The MLL (mixed lineage leukemia) gene forms chimeric fusions with a diverse set of partner genes as a consequence of chromosome translocations in leukemia. In several fusion partners, a transcriptional activation domain appears to be essential for conferring leukemogenic capacity on MILL protein. Other fusion partners, however, lack such domains. Here we show that gephyrin (GPHN), a neuronal receptor assembly protein and rare fusion partner of MLL in leukemia, has the capacity as an MLL-GPHN chimera to transform hematopoietic progenitors, despite lack of transcriptional activity. A small 15-amino acid tubulin-binding domain of GPHN is necessary and sufficient for this activity in vitro and in vivo. This domain also confers oligomerization capacity on MLL protein, suggesting that such activity may contribute critically to leukemogenesis. The transduction of MLL-GPHN into hematopoietic progenitor cells caused myeloid and lymphoid lineage leukemias in mice, suggesting that MLL-GPHN can target multipotent progenitor cells. Our results, and other recent data, provide a mechanism for oncogenic conversion of MILL by fusion partners encoding cytoplasmic proteins. (C) 2004 by The American Society of Hematology.

DOI： 10.1182/blood-2003-11-3817

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記述言語：英語   出版者・発行元：CARDEN JENNINGS PUBL CO LTD  

The MLL gene is a major player in leukemia, particularly in infant leukemia and in secondary, therapy-related acute leukemia. The normal MLL gene plays a key role in developmental regulation of gene expression (including HOX genes), and in leukemia this function is subverted by breakage, recombination, and chimeric fusion with one of 40 or more alternative partner genes. In infant leukemias, the chromosome translocations involving MLL arise during fetal hematopoiesis, possibly in a primitive lymphomyeloid stem cell. In general, these leukemias have a very poor prognosis. The malignancy of these leukemias is all the more dramatic considering their very short preclinical natural history or latency. These data raise fundamental issues of how such divergent MLL chimeric genes transform cells, why they so rapidly evolve to a malignant status, and what alternative or novel therapeutic strategies might be considered. We review here progress in tackling these questions. Int J Hematol. 2003;78:390-401. (C) 2003 The Japanese Society of Hematology.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

Infant acute myeloid leukemia (AML) of less than 12 months old is generally characterized by a high incidence of acute monoblastic or myelomonoblastic leukemia with hyperleukocytosis and extramedullary involvement. Most of the leukemic cells have 11q23 translocations, which lead to the MLL gene rearrangements. The MLL gene rearrangements occur at a high frequency in monoblastic subtype, hyperleukocytosis or young age in infant AML. Compared with acute lymphoblastic leukemia, however, it remains unknown whether prenatal origin exists in the pathogenesis of infant AML. Recently, the treatment outcome of infant AML has been clarified by two study groups, which confirmed the effect of intensive chemotherapy including repeated cycles of cytarabine and anthracyclines for infant AML. Presence of the MLL gene rearrangements, gender, age and white blood cell count showed no influence on the outcome of infant AML. The allogeneic hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for infant AML when a matched related donor is available. Monitoring of minimal residual disease by real-time PCR is a useful technique to predict the outcome or efficacy of the treatment in infant AML. Although intensive chemotherapy and/or allogeneic HSCT have cured most AML infants, some still relapse and ultimately die. A need remains for future development by exploiting the unusual biologic properties of leukemic progenitor cells expressing the abnormal MLL gene product.

DOI： 10.1080/1042819031000063363

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CARDEN JENNINGS PUBL CO LTD  

The correlation between infant leukemia and in utero exposure to topoisomerase II (topo-II) inhibitor has been clarified. We examined the in vitro effect of topo-II inhibitor (etoposide) on cleavage of the MLL. gene in cord and peripheral blood mononuelcar cells (MNCs). Southern blot analysis showed cleavage of the MLL gene in peripheral blood MNCs of infants when the MNC's were exposed to etoposide. MNCs were incubated with etoposide at various concentrations (1 to 50 muM), and a ligation-mediated polymerase chain reaction (LM-PCR) was used to detect double strand breaks (DSBs) of DNA in intron 8 of the MLL breakpoint cluster region. PCR products obtained with LM-PCR were subcloned and sequenced to identify the breakpoint in the MLL gene. The PCR products indicated DSBs of the MLL gene were obtained without any difference in the incidence between 3 different samples (cord and peripheral blood from infants and children). Sequencing analysis showed that the DSBs occurred on the telomeric side of intron 8 and near exon 9. There was no evidence that the cord blood was more susceptible to MLL DNA breakage by topo-II inhibitor than were other cells, Instability of the partner gene during the fetal period could be associated with the pathogenesis of infant leukemia.

DOI： 10.1007/BF02982722

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本小児血液・がん学会  

造血器腫瘍の病型特異的染色体転座から多くの融合遺伝子が単離されてきた.それらの融合遺伝子は, 転写因子やチロシンキナーゼなど血液細胞の分化・増殖に重要な遺伝子をその構成要素として含んでいることが多い.これらの遺伝子がその機能ドメインの一部を失い, あるいは他遺伝子の機能ドメインと結合することによって, 新たな融合蛋白が産生される.蛋白本来の機能を喪失あるいは異常機能を獲得した融合蛋白は血液細胞の分化阻害, 増殖能亢進またはアポトーシス抑制などの機能を血液細胞に付与し, 最終的に腫瘍化へと導く.融合遺伝子の機能解析は白血病化機構の解明のみならず, 新たな治療法の開発につながる重要な情報を多く提供してきた.また融合遺伝子の形成機構を知ることは白血病の発症予防の観点からも重要である.本総説では代表的な融合遺伝子を例に, 遺伝子異常による腫瘍化のメカニズムとその現時点での臨床応用を解説する.

DOI： 10.11412/jjph1987.15.427

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

We report a novel MLL-associated chromosome translocation t(11;14)(q23;q24) in a child who showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy, that included the topoisomerase-II inhibitor VP 16. Screening of a cDNA library of the patient's leukemic cells showed a novel fusion transcript between MLL and the Gephyrin (GPHN) gene on 14q24. The resulting MLL-GPHN fusion gene encodes MLL AT hook motifs and a DNA methyltransferase homology domain fused to the C-terminal half of Gephyrin, including a presumed tubulin binding site and a domain homologous to the Escherichia coli molybdenum cofactor biosynthesis protein MoeA. Genomic breakpoint analysis showed potential, in vitro topoisomerase-II DNA-binding sites spanning the breakpoints in both MLL and GPHN but no flanking sequences that might mediate homologous recombination. This suggests that MLL-GPHN may have been generated by VP 16/topoisomerase-II-induced DNA double-strand breaks, followed by error-prone DNA repair via non-homologous end joining. Gephyrin was originally identified as a submembraneous scaffold protein that anchors and immobilizes postsynaptic membrane neurotransmitter receptors to underlying cytoskeletal elements. It also is reported to bind to phosphatidylinositol 3,4,5-triphosphate binding proteins involved in actin dynamics and downstream signaling and, interacts with ATM-related family member RAFTI. Gephyrin domains in the chimeric protein therefore could contribute novel signal sequences or might modify MLL activity by oligomerization or intracellular redistribution. (C) 2001 Wiley-Liss, Inc.

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記述言語：英語   出版者・発行元：WILEY-LISS  

DOI： 10.1002/mpo.1223

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC HEMATOLOGY  

TEL-AML1 fusion resulting from the t(12; 21)(p13;q22) is one of the most common genetic abnormalities in childhood acute lymphoblastic leukemia. Recent findings that site-specific cleavage of the MLL gene can be induced by chemotherapeutic agents such as topoisomerase-ll inhibitors suggest that apoptogenic agents can cause chromosomal translocations in hematopoietic cells, This study demonstrates a possible relationship between exposure to apoptogenic stimuli, TEL breaks, and the formation of TEL-AML1 fusion in immature B lymphocytes, Short-term culture of immature B cell lines in the presence of apoptogenic stimuli such as serum starvation, etoposide, or salicylic acid induced double-strand breaks (DSBs) in intron 5 of the TEL gene and intron 1 of the AML1 gene. TEL-AML1 fusion transcripts were also identified by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in cell lines treated by serum starvation or aminophylline. DSBs within the TEL gene were also associated with fusion to other unknown genes, presumably as a result of chromosomal translocation. We also examined 67 cord blood and 147 normal peripheral blood samples for the existence of inframe TEL-AML1 fusion transcripts. One cord blood sample (1.5%) and 13 normal peripheral blood samples (8.8%) were positive as detected by nested RT-PCR, These data suggest that breakage and fusion of TEL and AML I may be relatively common events and that sublethal apoptotic signals could play a role in initiating leukemogenesis via the promotion of DNA damage. (C) 2001 by The American Society of Hematology

DOI： 10.1182/blood.V97.3.737

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

We analyzed 32 patients with various hematological malignancies including acute myelocytic leukemia and non-Hodgkin lymphoma with a breakpoint at 11q22-q25 of chromosome 11, but who did not have rearrangements of the MLL/ALL-1 gene. The breakpoint in each patient was identified by fluorescence in situ hybridization using 21 cosmid probes and 2 YAC probes. Breakpoints for each "rearrangement" involving translocations such as t(1;11), t(2;11), inv(11), t(11;15), and t(10;11) found in 5 of the 11 patients had breakpoints in a small region from Cc111-430 to Cc111-526 at 11q22-q23.1. Furthermore, breakpoints for chromosome deletions at 11q21-q23 in 10 patients were located in the same region as that of translocations. A commonly deleted region among 8 patients was identified from Cc111-526 to Cc111-555 at 11q23.1. Fluorescence in situ hybridization analysis revealed that breakpoints for additive chromosome [add(11)] aberrations, which had additional material of unknown origin at 11q23 to 11925 in 11 patients, were not located at 11q23 but rather at the more telomeric site of Cc111-503 to VIJ(2)2072 at 11q25. These results indicated that the patients had several restricted breakpoint sites, which means that these chromosomal regions have recurrent oncogenes and tumor suppressor genes for pathogenesis for leukemia and lymphoma. (C) 2001 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0165-4608(00)00316-2

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(株)医薬ジャーナル社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC HEMATOLOGY  

The ETV6/TEL gene has been reported to fuse to PDGFR beta b MDS1/EVI1, BTL, ACS2, STL, JAK2, ASL, CDX2, TRKC, AML1, and MN1. Among them, PDGFR beta, ASL, JAK2, and TRKC are tyrosine kinases (TK), We identified a novel ETV6 partner gene, ARG (ABL-related gene or ASL2), another TK gene in a cell line established from a patient with acute myelogenous leukemia (AML-MB) with a t(15;17)(q22;q11.2) and a t(1;12)(q25;p13), which has the remarkable feature to differentiate to mature eosinophils in culture with all-trans retinoic acid and cytokines, The ETV6/ARG transcripts consisted of exon 1 to 5 of ETV6 and the 3' portion of ARG starting from exon IB or exon 2, resulting in an open reading frame for a fusion protein consisting of the entire PNT oligomerization domain of ETV6 and all of the functional domains of ARG including the TK domain. This is the same protein structure as identified In the other ETV6 TK fusion proteins. The reciprocal ARG/ETV6 transcript was not expressed, and the normal ETV6 allele was not deleted or rearranged. Although the ABL Is known to be involved in various human malignancies, ARG has not been involved in human malignancies despite its high homology to ASL, Thus, this Is the first report showing involvement of ARG in human leukemia, The ETV6/ARG protein may be involved in the unique differentiation capacity of this cell line. (C) 2000 by The American Society of Hematology.

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その他リンク： http://orcid.org/0000-0001-6097-2803

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC HEMATOLOGY  

Chromosome translocations involving band 12p13 are known to be involved in a variety of hematologic malignancies, some of them resulting in rearrangement of the ETV6/TEL gene. Applying the fluorescence in situ hybridization (FISH) method, we found a cryptic translocation t(12;15)(p13;q25) in an adult acute myeloid leukemia (AML) patient. Hybridization with cosmid probes showed that the ETV6 gene was rearranged in this translocation. A patient-specific cDNA library was screened with ETV6 cDNA, and a novel fusion transcript was identified between the ETV6 and TRKC/NTRK3 gene located on 15q25. TRKC is a receptor tyrosine kinase that is activated by neurotrophin-3 (NT-3). It is known to be expressed broadly in neural tissues but not in hematologic cells, so far. ETV6-TRKC chimeric transcript encoded the pointed (PNT) domain of the ETV6 gene that fused to the protein-tyrosine kinase (PTK) domain of the TRKC gene. Two types of fusion transcript were determined, one that included the entire PTK domain of TRKC and the other in which the 3'-terminal 462 bp of TRKC was truncated within the PTK domain. Western blot analysis showed the expression of both chimeric proteins of 52 and 38 kD in size. Our results suggest that chimeric PTK expressed in the leukemic cells may contribute to cellular transformation by abnormally activating TRK signaling pathways. Moreover, this is the first report on truncated neurotrophin receptors associated in leukemia. (C) 1999 by The American Society of Hematology.

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記述言語：英語   出版者・発行元：W B SAUNDERS CO  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI IRELAND LTD  

Fluorescence in situ hybridization (FISH) analysis was applied to detect t(12;21) using two yeast artificial chromosome probes and cosmid probes covering the TEL(ETV6) and the AML1 gene to clarify the incidence of abnormality of t(12;21) in Japanese childhood acute lymphoblastic leukemia (ALL), We detected seven TEL/AML1 fusion positive patients (9.5%), all of whom were diagnosed as B-lineage ALL, among 74 childhood ALL. On the other hand, no TEL/AML1 fusion positive patients were found among 37 adult ALL. The incidence among Japanese seemed to be lower than that among other nations, Of the seven patients with the TEL/AML1 fusion, five exhibited normal karyotype, one was t(8;12)(q11;p13), i(21q) and the remaining one exhibited a near-triploid karyotype in conventional G-banding, The FISH method clearly demonstrated that all patients with the TEL/AML1 fusion had subpopulations of leukemic cells with deletion of the normal TEL allele, which is significant for understanding the progression of leukemia with t(12;21).

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記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

症例は42歳，女性。Etoposide 1,500 mgを含む化学療法により，malignant lymphoma, follicular, small cleaved cellは，第二寛解状態であった。4年4カ月後，dup(11)(q21q23)&amp;times;2を有するrefractory anemia with excess of blasts (RAEB)を発症し，急性骨髄性白血病(AML)-M5bに移行した。その後，RAEBまで改善したが，del(20)(q11q13.1)の付加的異常を有するクローンが出現し，AML-M6に移行した。MLL遺伝子は再構成しており，MLL遺伝子の5&#039;末と3&#039;末を用いたFISH解析では両シグナル間の解離を認めた。RT-PCRではexon 2からexon 8のtandem duplicationを認め，本例のMLL遺伝子や11q23の異常形成機序の一つと考えられた。

DOI： 10.11406/rinketsu.39.1163

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記述言語：日本語   出版者・発行元：(株)南江堂  

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Recent advances in molecular biological techniques have contributed to the tremendous progression made in the field of diagnosis of leukemia. Discovery of T- or B-lymphocyte associated genes, tumor specific genes and genes involved in chromosomal translocation has made it possible to detect leukemia cells by Southern blotting, PCR, RT-PCR or fluorescence in situ hybridization (FISH). The recently developed FISH is a simple, rapid and accurate method and requires a very small amount of specimen (about 500-1000 cells). It is possible to obtain results within 48 hours of sampling. This lecture were focused on two topics; 1) The application of FISH method in the diagnosis of leukemia using three types of probes (whole chromosome painting probe, centromeric probes and oncogene specific probes) and their combinations. 2) Clarification of concepts made by molecular biology especially in Philadelphia chromosome positive leukemia, Ph-negative chronic myelocytic leukemia, endemic/sporadic type of Burkitt&#039;s lymphoma, biphenotypic leukemia and leukemia with specific translocations.

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記述言語：日本語   出版者・発行元：(株)東京医学社  

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Leukemia-specific chromosomal aberrations are the most reliable tumor markers. Although chromosome analysis is a powerful diagnostic tool, some aberrations like monosomy 7 in AML, 15; 17 translocation in APL and trisomy 12 in CLL are not adequately detected. Fluorescence in situ hybridization is a recent method to detect specific genetic alteration in both interphase and mitoic cells and overcomes the disadvantages of conventional cytogenetics, Southern blotting and RT-PCR. In this manuscript, the advantages and limitations of the methods used for detecting leukemia/lymphoma specific chromosomal markers were discussed.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ Publishing Group  

A girl with intractable epilepsy who received high dose valproic acid showed bone marrow suppression, which improved after the end of valproic acid treatment and the administration of supportive treatments. Valproic acid markedly suppressed the in vitro colony growth in this patient. It is believed that high dose valproic acid treatment directly suppressed the growth of haematopoietic progenitors, resulting in bone marrow failure.

DOI： 10.1136/adc.71.2.153

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語  

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記述言語：英語   会議種別：ポスター発表  

researchmap

記述言語：日本語  

researchmap

記述言語：日本語  

researchmap

記述言語：英語   会議種別：ポスター発表  

researchmap

記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

researchmap

記述言語：英語  

researchmap

記述言語：日本語  

researchmap

記述言語：日本語   会議種別：口頭発表（一般）  

researchmap

記述言語：日本語  

researchmap

記述言語：日本語  

researchmap

記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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