Molecular mechanisms of blast crisis transition and maintenance of leukemic stem cells in chronic myelogenous leukemia

慢性粒细胞白血病急变期和白血病干细胞维持的分子机制

• 批准号: 23791074
• 负责人: NAKAHARA Fumio
• 金额: $ 2.83万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23791074/
• 关键词: 白血病; 白血病幹細胞; 慢性骨髄性白血病; 急性転化

High levels of Hes1 expression are frequently found in BCR-ABL-positive chronic myelogenous leukemia in blast crisis (CML-BC). In mouse bone marrow transplantation (BMT) models, co-expression of BCR-ABL and Hes1 induces CML-BC-like disease; however the underlying mechanism remained elusive. Here, based on gene expression analysis, we show that MMP-9 is upregulated by Hes1 in common myeloid progenitors (CMPs). Analysis of promoter activity demonstrated that Hes1 upregulated MMP-9 by activating NF-kB. Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of Hes1 expression. Interestingly, MMP-9 deficiency impaired the cobblestone area-forming ability of CMPs expressing BCR-ABL and Hes1 that were in conjunction with a stromal cell layer. In addition, these CMPs secreted MMP-9, promoting the release of soluble Kit-ligand (sKitL) from stromal cells, thereby enhancing proliferation of the leukemic cells. In accordance, mice transplanted with CMPs expressing BCR-ABL and Hes1 exhibited high levels of sKitL as well as MMP-9 in the serum. Importantly, MMP-9 deficiency impaired the development of CML-BC-like disease induced by BCR-ABL and Hes1 in mouse BMT models. Thus, Hes1 promotes the development of CML-BC, partly through MMP-9 upregulation in leukemic cells.

BCR-ABL阳性的慢性粒细胞白血病急变期(CML-BC)常有Hes1的高表达。在小鼠骨髓移植(BMT)模型中，bcr-abl和Hes1共表达可诱导CML-BC样病，但其机制尚不清楚。在这里，基于基因表达分析，我们发现在常见的髓系祖细胞(CMPS)中，基质金属蛋白酶-9被Hes1上调。启动子活性分析表明，Hes1通过激活NF-kB上调了基质金属蛋白酶-9的表达。对20例CML-BC患者标本的分析表明，3例CML-BC患者的MMP9高表达，2例Hes1高表达。有趣的是，基质金属蛋白酶-9缺乏削弱了表达BCR-ABL和Hes1的CMP与基质细胞层结合的鹅卵石区域形成能力。此外，这些CMPS还分泌基质金属蛋白酶-9，促进基质细胞释放可溶性Kit-L，从而促进白血病细胞的增殖。相应地，移植了表达bcr-abl和hes1的CMPS的小鼠显示出血清中sKitL和MMP-9的高水平。重要的是，MMP9缺乏可抑制BCR-ABL和Hes1诱导的小鼠骨髓移植模型中CML-BC样病的发生。因此，Hes1促进了CML-BC的发展，部分是通过上调白血病细胞中的MMP-9来实现的。

项目成果

Molecular mechanisms underlying leukemic transformation of myelodysplastic syndromes (MDS) and chronic myelogenous leukemia (CML)

骨髓增生异常综合征（MDS）和慢性粒细胞白血病（CML）白血病转化的分子机制

• 发表时间: 2012
• 期刊: Rinsho Ketsueki
• 作者: Kitamura T;Watanabe-Okochi N;InoueD;Togami K;Uchida T;Kagiyama Y;Kawabata K;Chiba S;Harada Y;Harada H;Kitaura J and Nakahara F
• 通讯作者: Kitaura J and Nakahara F

A Soluble Form of LMIR5/CD300b Amplifies Lipopolysaccharide-Induced Lethal Inflammation in Sepsis

• DOI: 10.4049/jimmunol.1201139
• 发表时间: 2012-07
• 期刊: The Journal of Immunology
• 作者: Y. Yamanishi;Mariko Takahashi;Kumi Izawa;Masamichi Isobe;S. Ito;Akiho Tsuchiya;Akie Maehara;Ayako Kaitani;Tomoyuki Uchida;K. Togami;Y. Enomoto;F. Nakahara;T. Oki;M. Kajikawa;H. Kurihara;T. Kitamura;J. Kitaura

Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models

• DOI: 10.1007/s12185-011-0994-5
• 发表时间: 2012-02-01
• 期刊: INTERNATIONAL JOURNAL OF HEMATOLOGY
• 影响因子: 2.1
• 作者: Doki, Noriko;Kitaura, Jiro;Kitamura, Toshio
• 通讯作者: Kitamura, Toshio

Molecular Mechanisms of blast crisis in chronic myelogenous leukemia caused by upregulation of Hes1

Hes1上调引起慢性粒细胞白血病急变的分子机制

• 发表时间: 2012
• 作者: 中原史雄;北浦次郎;川畑公人;内田智之,鍵山侑希;井上大地;戸上勝仁;沖俊彦;原田結花 ;原田浩徳 ;北村俊雄
• 通讯作者: 北村俊雄

Transforming growth factor-beta-stimulated clone-22 is a negative-feedback regulator of Ras / Raf signaling: Implications for tumorigenesis

转化生长因子-β 刺激的克隆 22 是 Ras / Raf 信号传导的负反馈调节器：对肿瘤发生的影响

• 发表时间: 2012
• 期刊: Cancer Sci
• 影响因子: 5.7
• 作者: Nakamura M;Kitaura J;Enomoto Y;Lu Y;Nishimura K;Isobe M;Ozaki K;Komeno Y;Nakahara F;Oki T;Kume H;Homma Y and Kitamura T
• 通讯作者: Homma Y and Kitamura T