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Mechanism of leukemogenesis by constitutive active receptor tyrosine kinase

组成型活性受体酪氨酸激酶导致白血病的机制

基本信息

批准号：
16590938
负责人：
MIZUKI Masao
金额：
$ 2.3万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590938/
关键词：
c-Kit FLT3 leukemia AML signal transduction oncogenesis chaperone activation loop 分子標的療法チロシンキナーゼ急性骨髄性白血病活性化変異 c-Kit tyrosine kinase oncogene leukemia mutation chaperone

项目摘要

Constitutive active mutants of tyrosine kinases are the key genetic abnormality of cancer. In hematological malignancies, constitutive active mutants of receptor tyrosine kinases such as c-Kit and FLT3 have been identified as the critical mutations in acute myeloid leukemia. We have studied the mechanism of leukemogenesis by these constitutive active receptor tyrosine kinases. Since tyrosine residues in the cytoplasmic domain of receptor tyrosine kinases regulate the activation and the downstream signal transduction, we investigated the critical tyrosine residues which regulate the constitutive activation of mutant receptor tyrosine kinases. By analyzing the Tyr-Phe mutations of each 22 tyrosine residue of FLT3 Asp838Val, constitutive active mutant of FLT3, we identified that Tyr845,Tyr892, and Tyr922 are the critical tyrosine residues which regulated the activation of FLT3Asp835Val mutant. The Tyr 845Phe,Tyr892Phe and Tyr922Phe mutations abolished the kinase activation itself of FLT3 Asp835Val, leading to the inhibition of full signal transduction, proliferation and survival. The suppressed kinase activity of these Tyr-Phe mutants were partially rescued by shifting the temperature to 33℃, and co-expression of chaperone proteins, Cdc38 and Hsp90. These results suggested that Tyr845,Tyr892 and Tyr922 may be the critical tyrosine residues which maintain the active conformation of FLT3 Asp835Val mutant. We have already identified that the tyrosine residue, Tyr7l9,critically regulated the activation of c-Kit Asp8l4Val mutant, which is the corresponding mutant to FLT3 Asp835Val. Taken together, the constitutive active mutants of receptor tyrosine kinase have the specific tyrosine residues which regulate the oncogenic activation, which may serve as the new specific targets of tyrosine kinase inhibitors.

酪氨酸激酶组成型活性突变体是肿瘤的关键遗传异常。在恶性血液病中，受体酪氨酸激酶如c-Kit和FLT 3的组成型活性突变体已被确定为急性髓性白血病中的关键突变。我们已经研究了这些组成性活性受体酪氨酸激酶的白血病发生机制。由于受体酪氨酸激酶胞质结构域中的酪氨酸残基调节激活和下游信号转导，我们研究了调节突变型受体酪氨酸激酶组成性激活的关键酪氨酸残基。通过分析FLT 3 Asp 835 Val突变体的22个酪氨酸残基的Tyr-Phe突变，我们确定Tyr 845、Tyr 892和Tyr 922是调控FLT 3 Asp 835 Val突变体激活的关键酪氨酸残基。Tyr 845 Phe、Tyr 892 Phe和Tyr 922 Phe突变消除了FLT 3 Asp 835 Val的激酶激活本身，导致完全信号转导、增殖和存活的抑制。这些Tyr-Phe突变体被抑制的激酶活性通过将温度转移到33℃并共表达伴侣蛋白Cdc 38和Hsp 90而部分得到拯救。这些结果表明Tyr 845、Tyr 892和Tyr 922可能是维持Asp 835 Val突变体活性构象的关键酪氨酸残基。我们已经确定，酪氨酸残基Tyr 719，关键调节c-Kit Asp 814 Val突变体的激活，该突变体是FLT 3 Asp 835 Val的相应突变体。因此，受体酪氨酸激酶组成型活性突变体具有特异性的酪氨酸残基，这些残基可调控肿瘤的活化，有望成为酪氨酸激酶抑制剂的新的特异性靶点。

项目成果

期刊论文数量（46）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Distinct role for c-kit receptor tyrosine kinase and SgIGSF adhesion molecule in attachment of mast cells to fibroblasts

DOI：
10.1038/labinvest.3700231
发表时间：
2005-03-01
期刊：
LABORATORY INVESTIGATION
影响因子：
5
作者：
Koma, Y;Ito, A;Kitamura, Y
通讯作者：
Kitamura, Y

Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease

DOI：
10.1182/blood-2004-12-4602
发表时间：
2005-10-15
期刊：
BLOOD
影响因子：
20.3
作者：
Nishimoto, N;Kanakura, Y;Kishimoto, T
通讯作者：
Kishimoto, T

NF-kappaB family proteins participate in multiple steps of hematopoiesis through elimination of reactive oxygen species.

DOI：
发表时间：
2004
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Soichi Nakata;I. Matsumura;Hirokazu Tanaka;S. Ezoe;Yusuke Satoh;J. Ishikawa;T. Era;Y. Kanakura
通讯作者：
Soichi Nakata;I. Matsumura;Hirokazu Tanaka;S. Ezoe;Yusuke Satoh;J. Ishikawa;T. Era;Y. Kanakura

Gastrointestinal stromal tumor(GIST) : From pathology to molecular target therapy. (chapter ; KIT mutations in hematopoietic malignancies)(Edited by Kitamura Y, Miettinenn M, Hirota S and Kanakura Y)

胃肠道间质瘤（GIST）：从病理学到分子靶向治疗。