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開催日時: 2018年7月30日 15:00 ~ 16:00
開催場所: 2号館2階 大講義室
講師: 講師1 合山 進
講師2 Jaroslaw P. Maciejewski
所属: 講師1 東京大学医科学研究所 先端医療研究センター 細胞療法分野・准教授
講師2 Professor and Chairman, Translational Hematology and Oncology Department Taussig Cancer Center, Cleveland Clinic Cleveland, Ohio
演題: 1.Therapy-resistant leukemia stem cells in acute myeloid leukemia
2.Early clonal events determine hierarchical progression in myeloid neoplasia: impact on resulting morphologic features.

1.The leukemia stem cell (LSC) model has received considerable attention in the past 20 years with the identification of rare cell populations expressing stem cell markers in leukemia cell populations. LSCs are thought to be responsible for leukemia initiation, recurrence, and drug resistance, thus being regarded as excellent targets for developing curative therapies. However, characters of LSCs that are resistant to specific types of therapies have not been fully understood. Using a mouse model for myeloid leukemia, we found that a p53-Mdm2 interaction inhibitor (DS-5272) showed the robust anti-leukemia effect against MLL-AF9 leukemia in vivo. Nevertheless, all mice eventually developed leukemia, indicating the existence of therapy-resistant LSCs. These LSCs were relatively enriched within the bone marrow (BM) endosteal region where osteoblasts reside, and expressed higher levels of Hif1 and PD-L1. The antileukemia effect of DS-5272 was markedly attenuated in immunodeficient mice, indicating the critical impact of systemic immune responses that drive p53-mediated leukemia suppression. Furthermore, inhibition of Hif1 and PD-L1 sensitized leukemia cells to DS-5272. Our study showed the potent activity of a p53-MDM2 interaction inhibitor against MLL-fusion leukemia, which is further augmented by antitumor immunity.

2.Myelodysplastic syndromes (MDS) arise in the elderly through stepwise acquisitions of many possible somatic mutations. The clinical diversity of this disease reflects heterogeneity of the resulting clonal architecture. Through analysis of 1,809 MDS patients (of which over 150 were studied serially), we demonstrate using specifically developed bio-statistical/analytic pipeline that the ancestral hits are mutually exclusive and defining of subsequent evolution not via a random, but rather preferential acquisition of specific secondary mutations. We have also objectively digitalized major morphologic features including the presence of various forms of dysplasia, cytopenia and myeloproliferative features (monocytosis, fibrosis increased megakaryocytes) obtained through a uniform unbiased and blinded pathologic evaluation. These features have been correlated with the presence of specific mutations and common mutational combinations. A number of important relationships between specific morphologic profiles and mutation combinations have been uncovered allowing to determine predictive value of morphologic configurations with regard to certain genotypes and vice versa. Similarly, our analysis revealed a convergence of molecular pathways steaming from distinct lesions towards common shared morphology. We also show that mutations in some genes exert different effects of the clinical features depending on their position in the clonal hierarchy. The latency between ancestral and secondary hits can be long, as evidenced by their presence in a prevalent condition known as clonal hematopoieisis of indeterminate potential (CHIP). Separating ancestral and secondary hits in MDS patients and comparing frequencies of mutations identified in meta-analysis of CHIP enabled us to speculate molecular and clinical characteristics of CHIP-related MDS and contrast them to MDS arising as de novo disease characterized by very penetrant mutations with a shorter latency to manifest disease. Patients with CHIP-related MDS had dominant TET2, DNMT3A and ASXL1 mutations, and overall higher mutational burden, were more elderly, exhibited less -7/del(7q) and complex karyotype, and showed better prognosis compared to those in CHIP-unrelated de novo MDS. In sum, we conclude that MDS patients can be broadly partitioned into pathogenically distinct CHIP-related vs. –unrelated MDS forms. Certain mutational configurations create morphologic configurations with subclonal hits further shaping the resultant morphology. Distinction of MDS by founder lesions and the presence of sweeping subclonal hits has wide-ranging therapeutic consequences.

世話人: 〇北村 俊雄(細胞療法分野)
 岩間 厚志(幹細胞分子医学分野)
開催日時: 2018年7月30日 14:00 ~ 15:00
開催場所: 2号館2階 大講義室
講師: 講師1 田久保 圭誉
講師2 Ravi Majeti
所属: 講師1 国立国際医療研究センター研究所 生体恒常性プロジェクト・プロジェクト長
講師2 Associate Professor of Medicine Chief, Division of Hematology Institute for Stem Cell Biology and Regenerative Medicine Stanford University School of Medicine
演題: 1.Functional alteration of hematopoietic stem cell niche during aging 
2.Stem Cells and Human AML

1.Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. A particular gap is our understanding of the age-related alteration of HSC niche, which bridges environmental cues to HSC aging. Recent studies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors required for HSC integrity at steady state and in stress. To approach aging-related alteration in HSC niche from a metabolic perspective, we recently took advantage of technical developments in metabolomics and in vivo imaging. In this mini-symposium, I will address the environmental regulation that tunes arrival of HSC to bone marrow after transplantation and its alteration during aging.

2.AML develops from the sequential acquisition of multiple mutations in a single lineage of cells. These mutations initially occur in HSCs, termed pre-leukemic HSCs, and are enriched in genes involved in regulation of the epigenome. The pre-leukemic cells acquire additional mutations, often in genes involved in proliferation, resulting in development of AML. Stratification of a cohort of AML patients into high or low pre-leukemic HSC groups demonstrated that the high group had much worse overall and relapse-free survival, indicating that the presence of pre-leukemic HSC may be critical for clinical outcomes. In bulk AML, sequencing studies demonstrated that most cases harbor multiple subclones with a complex evolutionary structure. These subclones potentially exhibit distinct features including leukemia stem cell properties, clonal dominance, and responses to chemotherapy and targeted agents. Isolating and investigating these subclones is essential to understanding their properties, and is facilitated by a novel humanized ossicle xenotransplantation model, single cell methods, and CRISPR/Cas9 engineering of normal and leukemic cells. Eventually, all subclones must be targeted in order to improve long-term outcomes and for potential cures in AML. Notably, mutation-specific targeted agents have the potential to improve outcomes in AML. Several approaches were employed to identify mutation-specific vulnerabilities including epigenomic profiling, computational approaches, and metabolomic profiling. Several targets were validated through genetic and/or pharmacologic modulation in primary AML cells and xenograft models, making them strong candidates for therapeutic development.

世話人: 〇岩間 厚志(幹細胞分子医学分野)
 北村 俊雄(細胞療法分野)
開催日時: 2018年7月11日 16:00  ~ 17:00
開催場所: 総合研究棟8階 大セミナー室
講師: 平田 真
所属: 東京大学医科学研究所ヒトゲノム解析センター シークエンス技術開発分野・特任研究員
演題: Common Diseaseの臨床情報解析とRare Diseaseのゲノム解析~個別化医療の実現を目指して~


世話人: 〇宮野 悟(DNA情報解析分野)
 柴田 龍弘(ゲノム医科学分野)
 井元 清哉 (健康医療データサイエンス)
開催日時: 2018年7月4日 17:00 ~ 18:00
開催場所: 病院棟8階 北大会議室
講師: 船引 宏則
所属: Professor and Head of Laboratory, The Rockefeller University, Laboratory of Chromosome and Cell Biology
演題: Regulations of mitotic processes by nucleosomes — molecular principles and implications in cancer biology and immunology

Chromosome structure and functions dramatically change during mitosis. Although the nucleosome is a fundamental structural and functional unit of eukaryotic chromatin, its regulatory roles in mitosis are poorly understood. Through comparative chromatin proteomics analysis to identify proteins whose chromatin binding is altered in mitosis, we discovered the novel nucleosome remodeling complex CHIRRC, composed of CDCA7 and HELLS (homolog of plant DDM1), both of which are mutated in the Immunodeficiency, Centromere instability and Facial anomalies (ICF) syndrome. Lymphoblastoid cell lines from ICF patients exhibit hypomethylation and fragility at juxtacentromeric heterochromatin of chromosome 1 and 16. Our finding provides a mechanistic insight into how CDCA7 and HELLS contribute to DNA methylation. We also found that the cytoplasmic DNA sensor, cGAS, a critical component of the innate immune system, gains an access to mitotic chromosomes upon nuclear envelope break down, but its DNA-induced activation is suppressed by the nucleosome. However, when cells are arrested in mitosis by taxol, cGAS slowly becomes activated and promotes apoptosis. Implications of these findings in the ICF syndrome and cancers will be discussed.

世話人: 〇中西 真 (癌防御シグナル分野)
 山梨 裕司 (腫瘍抑制分野)
開催日時: 2018年8月2日 16:00 ~ 17:00
開催場所: 1号館2階 2-3会議室
講師: 川上 正敬
所属: Instructor, MD Anderson Cancer Center, Department of Thoracic/Head and Neck Medical Oncology
演題: anaphase catastroph誘導によるがん治療の可能性

がん細胞はそのhallmarkとして知られる染色体不安定性を背景として、しばしば過剰な中心体を持つ。過剰中心体はaneuploidyを引き起こし、外的ストレスへの耐性や細胞増殖促進などがん細胞の生存に有利な特性をもたらす一方で、細胞分裂時の染色体の分離異常は細胞に有害である側面も持つ。我々は肺癌細胞においてCDK1/CDK2阻害により、細胞分裂の際に過剰中心体の二極への収束が阻害され、細胞の多極分裂とそれに伴う染色体分離異常を経て娘細胞にアポトーシスが誘導されることを明らかにし、これをanaphase catastropheと名付けた。CDK1/CDK2阻害によるanaphase catastropheの誘導は、過剰中心体を持たない正常細胞では回避され、がんに比較的に特異性を持つ治療戦略として期待できる。その分子メカニズムとして、中心体タンパクの一つであるCP110のリン酸化阻害を介することがわかった。興味深いことにCP110タンパクは KRASの活性化でユビキチン機構により不安定化し、そのためanaphase catastropheは特にKRAS変異のある肺癌細胞で誘導されやすい。anaphase catastropheの誘導は、肺癌のみならず膵癌や大腸癌、リンパ腫などでも確認された。本セミナーではanaphase catastropheについてこれまでにわかっている知見を紹介し、がん治療におけるこの機構の可能性を考察したい。

世話人: 〇北村 俊雄 (細胞療法分野)
 中西 真 (癌防御シグナル分野)
開催日時: 2018年7月23日 16:00 ~ 17:00
開催場所: 2号館小講義室
講師: 米原 圭祐
所属: オーフス大学ダンドライト研究所 准教授
演題: 視覚運動を検出するマウス神経回路の構造、機能、発達と疾患

視覚運動の方向や速度の検出は視覚系の重要な機能の一つであり、動物の生存にとって重要である。特定の方向の視覚運動に選択的に応答する神経細胞を方向選択性細胞と呼び、マウスやウサギを用いた研究から大脳視覚皮質のみならず 網膜にも方向選択性細胞が存在することが知られている。演者はこれまでマウス網膜をモデルとして方向選択性細胞の構造(文献1)や機能(文献2)、発達(文献3)を研究することにより、異なるタイプの神経細胞同士の相互作用がどのようにして感覚情報を処理するのかを明らかにしようとしてきた。最近では、網膜の方向選択性細胞の機能異常が先天性眼振という眼球運動の疾患に関連していることも明らかにした(文献4)。また、2015年からはデンマークで研究室を主宰し、2光子イメージング、電気生理、ウイルスベクターによる神経回路標識、分子生物学、マウス遺伝学などを組み合わせ、網膜で処理された視覚情報が下流の神経中枢においてさらにどのように処理されるのか(文献5、6)などを明らかにするべく研究を展開している。本セミナーでは、近年の我々の一連の取り組みを紹介し、また将来の展望を議論する。

世話人: 〇渡辺 すみ子 (再生基礎医科学)
 真鍋 俊也 (神経ネットワーク)
開催日時: 2018年6月20日 16:00 ~ 17:00
開催場所: 1号館2階 2-3会議室
講師: 坂田 義詞
所属: 東京大学 医科学研究所 先端医療研究センター 先端がん治療分野・特任研究員
演題: 増殖型遺伝子組換え単純ヘルペスウイルスG47Δを用いた肺癌のウイルス療法の開発


世話人: 〇北村 俊雄 (細胞療法分野)
 長村 文孝 (先端医療開発推進分野)

開催日時: 2018年7月18日 16:00 ~ 17:00
開催場所: 2号館 小講義室
講師: Paul A Ramsland
所属: School of Science, RMIT University・Principal Research Fellow
演題: Structural and computational studies of glycan targeting in cancer and infection

Carbohydrates (glycans) on the surface of cells present a complex code that can be recognized by a range of carbohydrate-binding proteins including antibodies and lectins. Blood group related glycans such as Lewis system antigens are often over-expressed by cancer cells and have been associated with tumour progression and invasiveness. On healthy and inflamed tissues similar Lewis glycans can become targets for bacterial adhesion. In this presentation, I will provide an overview of our structural studies using crystallography, automated docking and molecular dynamics that have probed recognition of Lewis system antigens by antibodies and lectins with implications for development of cancer-targeting antibodies and carbohydrate inspired anti-infectives. This work will be contrasted with recent crystal structures we have determined that define how a single antibody can bind a wide range of microbes through recognition of a common core oligosaccharide chain.

世話人: 〇長門石 曉(先進的バイオ医薬品学)
 古川 洋一(臨床ゲノム腫瘍学分野)
開催日時: 2018年6月14日 16:00 ~ 17:00
開催場所: 総合研究棟4階 会議室
講師: Mahesh Desai
所属: Principal Investigator Allergology - Immunology - Inflammation Research Unit Department of Infection and Immunity Luxembourg Institute of Health
演題: Diet-driven interactions of the gut microbiome with the intestinal mucus barrier

The functional interactions of the human gut microbiome with its host are largely driven by diet, yet the underlying mechanisms have remained poorly understood. By employing a gnotobiotic mouse model—containing a synthetic human gut microbiota composed of 14 commensal bacteria—we recently showed that a dietary fiber-deprived microbiota degrades the colonic mucus layer, which is the first line of defense against invading microorganisms. Furthermore, a fiber-deprived, mucus-eroding microbiota enhances susceptibility to the enteric pathogen Citrobacter rodentium (Desai et al. Cell (2016), 167, 1339–1353). Our follow-up experiments indicate that such deterioration of the colonic mucus barrier is associated with the immunological changes observed in inflammatory bowel disease. In the face of changing Western diets, our results suggest that dietary therapeutics, including next-generation prebiotics, could be utilized to modulate the the gut barrier alterations and to reduce the incidence of colitis.

世話人: 〇清野 宏 (粘膜免疫学部門)
 三宅 健介 (感染遺伝学分野)
開催日時: 2018年6月29日 15:00 ~ 16:00
開催場所: 総合研究棟4階会議室
講師: デニス・キャロル
所属: アメリカ国際開発庁・グローバル保健局・新興感染症室長
演題: グローバルヘルス・セキュリティーにおける新戦略『グローバル・バイローム・プロジェクト』~感染症対策の最前線~ 



世話人: 〇一戸 猛志(ウイルス学分野)
 河岡 義裕(ウイルス感染分野)