Developmental impact of MLL-AF4fusion gene on early hematopoieticstem cells

MLL-AF4融合基因对早期造血干细胞发育的影响

• 批准号: 22591162
• 负责人: EGUCHI Mariko
• 金额: $ 2.91万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22591162/
• 关键词: 小児腫瘍学; MLL; ES細胞; 造血細胞分化; 白血病

To study the developmental impact of MLL-AF4 fusion gene on early hematopoietic development, mouse embryonic stem (ES) cells with constitutive expression of MLL-AF4 were established. When hematopoietic differentiation was examined by embryoid body (EB) formation, Tie2^+c-kit^+cells which contain early hematopoietic stem cells were significantly reduced in MLL-AF4 expressing Ebs compared to that of control Ebs.Expression array analysis indicated that MLL-AF4 works as positive regulator of gene expression up-regulating various genes. Several genes up-regulated by MLL-AF4 were known to have important roles in cell differentiation to mesenchymal lineage, whereas transcriptional regulator of hematopoietic lineage were down-regulated. These MLL-AF4 expressing pre-hematopoietic stem cells with mesenchymal nature, were unable to cause leukemia in vitroor in vivo, showing that some secondary event is necessary to cause leukemia. MLL-AF4, having the potential to influence early hematopoietic cell differentiation, may cause leukemic transformation whenaccompanied by some important additional genetic events.

为了研究MLL-AF4融合基因对早期造血发育的发育影响，建立了具有MLL-AF4组成型表达的小鼠胚胎茎（ES）细胞。当通过胚胎体（EB）形成检查造血分化时，含有早期造血干细胞的TIE2^+C-KIT^+细胞在表达EBS的MLL-AF4中显着降低了与对照EBS的MLL-AF4相比。表达阵列分析表明，MLL-AF4可作为Gene表达各种基因的阳性调节剂。已知通过MLL-AF4上调的几个基因在分化与间充质谱系的细胞分化中具有重要作用，而造血谱系的转录调节剂则下降。这些表达具有间充质性质的脊髓脊髓干细胞的MLL-AF4无法在体内引起白血病，表明某些次要事件是引起白血病的必要事件。 MLL-AF4有可能影响早期造血细胞分化的潜力，可能会在某些重要的其他遗传事件中compan时会导致白血病转化。

项目成果

Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements

• DOI: 10.1038/leu.2012.242
• 发表时间: 2013-02-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Nishi, M.;Eguchi-Ishimae, M.;Eguchi, M.
• 通讯作者: Eguchi, M.

MicroRNA let-7b is a target of leukemogenic MLL fusion protein and in activated by DNA hyper-methylation

MicroRNA let-7b 是致白血病 MLL 融合蛋白的靶标，可通过 DNA 高甲基化激活

• 发表时间: 2011
• 作者: 尾路祐介;福田菜莉;森井英一;辰己直也;北条 望;村上由衣;斉藤千紗恵;鈴木望友;川田紗世;澄川美穂子;坪井昭博;岡 芳弘;杉山治夫;石前(江口)峰斉
• 通讯作者: 石前(江口)峰斉

MicroRNA let-7b is a target of leukemogenic MLL fusion protein and inactivated by DNA hyper-methylation

MicroRNA let-7b 是致白血病 MLL 融合蛋白的靶标，可通过 DNA 高甲基化灭活

• 发表时间: 2011
• 作者: 石前峰斉;江口真理子;西 真範;田内久道;河上早苗;杉田完爾;石井榮一
• 通讯作者: 石井榮一

Clinical features and outcome of X-linked lymphoproliferative syndrome type 1 (SAP deficiency) in Japan identified by the combination of flow cytometric assay and genetic analysis

• DOI: 10.1111/j.1399-3038.2012.01282.x
• 发表时间: 2012-08-01
• 期刊: PEDIATRIC ALLERGY AND IMMUNOLOGY
• 影响因子: 4.4
• 作者: Kanegane, Hirokazu;Yang, Xi;Miyawaki, Toshio
• 通讯作者: Miyawaki, Toshio

ETV6-ARNT fusion in a patient with childhood T lymphoblastic leukemia

• DOI: 10.1016/j.cancergencyto.2010.07.121
• 发表时间: 2010-10-01
• 期刊: CANCER GENETICS AND CYTOGENETICS
• 作者: Otsubo, Keisuke;Kanegane, Hirokazu;Miyawaki, Toshio
• 通讯作者: Miyawaki, Toshio