AML1 complex as a molecular target for leukemia therapy

AML1复合物作为白血病治疗的分子靶点

基本信息

批准号：
15390033
负责人：
KITABAYASHI Issay
金额：
$ 9.41万
依托单位：
National Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390033/
关键词：
Leukemia MOZ histone acetyltransferase hematopoiesis transcription regulation AML1 stem cells HIPK2 白血病染色体転座タンパク質リン酸化 PML nuclear body chromosome translocation cell differeniation

项目摘要

The genes encoding the AML1/CBFβ transcription factor complex are the most frequent targets of chromosome translocations found in human leukemia. We previously purified AML1 complexes, and found that the complex contains histone acetyltransferases such as p300 and MOZ, promyelocytic leukemia isoform I (PML I), and a protein kinase (HIPK2). The genes encoding AML1 and some of the AML1-interacting proteins are the targets of leukemia-associated chromosome translocations, suggesting that common pathways may be shared by distinct myeloid malignancies and underscores the importance of this complex in hematopoiesis and leukemogenesis. HIPK2 formed a complex with AML1 and p300, and phosphorylated both AML1 and p300 to stimulate both transcription activation and HAT activities. Phosphorylation of p300 was triggered by phosphorylated AML1 as well as by PU.1, c-MYB, c-JUN, and c-FOS, and was inhibited by dominant-negative HIPK2. Phosphorylation of p300 and AML1 was impaired in Hipk1/2 double-def … More icient mouse embryos. Double-deficient mice exhibited defects in primitive/definitive hematopoiesis, vasculogenesis, angiogenesis and neural tube closure. These phenotypes are in part similar to those observed in p300- and CBP-deficient mice. HIPK2 also phosphorylates another co-activator, MOZ, in an AML1-dependent manner. These results suggest a novel mechanism by which transcription factors could regulate local histone acetylation and transcription of their target genes. To investigate the roles of MOZ in normal hematopoiesis, we generated MOZ-null mice. MOZ^<-/-> mice died around E15. In MOZ^<-/-> E14.5 embryos, hematopoietic stem cells, lineage-committed progenitors and B lineage cells were severely reduced. On the other hand, arrest of erythroid maturation and elevated myeloid lineage populations were observed. MOZ-deficient fetal liver cells could not reconstitute hematopoiesis of recipients after transplantation. Analysis using microarray and flow cytometry revealed that expression of thrombopoietin receptor (c-Mpl), HoxA9 and c-Kit was down-regulated. These results show that MOZ is required for maintenance of hematopoietic stem cells and that it plays a role in differentiation of erythroid and myeloid cells. Less

编码AML1/CBFβ转录的基因是人类白血病中发现的最常见的染色体易位。 . The Genes Encoding AML1 AML1-Interacting Proteins Is The Targets of Leukemia-Associated Crumosome Slocations, Surgesting that Common Pathways May Be Shared by Distinct Myeloid MalignNCIES AND UNDERSCORES THE IMPORTANCE OF THIS COMPLEX in Hematopoiesis and Leukemogenesis. Ctivation and Hat Activities. Phosphorylation of P300由磷酸化的AML1以及PU.1，C-Myb，C-Jun和C-Fos触发，并在HIPK1/2双DEF中受到了p300和AML1的抑制。 ..胚胎中的双重缺陷小鼠在原始 /确定的造血，血管生成，血管生成和神经管闭合部分 - 这些结果表明，转录因子可以局部组成，我们的靶代蛋白会产生moz-Z-null小鼠E14.5胚胎，造血干细胞，谱系的祖细胞和B谱系细胞被降低。这些结果表明，维持造血干细胞需要MOZ，并且在分化红细胞和髓样细胞中起作用

项目成果

期刊论文数量（30）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutations and deletions of the CBP gene in human lung cancer.

DOI：
发表时间：
2005-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
M. Kishimoto;T. Kohno;K. Okudela;A. Otsuka;H. Sasaki;C. Tanabe;T. Sakiyama;C. Hirama;I. Kitabayashi;J. Minna;S. Takenoshita;J. Yokota
通讯作者：
M. Kishimoto;T. Kohno;K. Okudela;A. Otsuka;H. Sasaki;C. Tanabe;T. Sakiyama;C. Hirama;I. Kitabayashi;J. Minna;S. Takenoshita;J. Yokota

MLL forms f SETI-like histone methyltransferase complex with menin to regulate Hox gene expression.

MLL 与 menin 形成 f SETI 样组蛋白甲基转移酶复合物来调节 Hox 基因表达。