Analysis of the biojogicel effect of the nudeophcsmin gene mutation on development and progression of leukemia

Nudophcsmin基因突变对白血病发生发展的影响分析

• 批准号: 18591054
• 负责人: KIYOI Hitoshi
• 金额: $ 2.51万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591054/
• 关键词: leukemia; Nucleouhosmin; mutation; signal transduction

Mutation of the nucleophosmin(NPMI) gene is found in about 30% of acute myeloid leukemia(AMC) patients, and is closely associated with the cemplete remission rate and a long-term survival rate. In addition, it has been reported that lower expression level of the NPM1 gene causes the development of myelodysplastic syndrome (MDS). Therefore, NPM seems to play an important role for the development and progression of AML and MDS. To date, several genetic alterations have been reportedly involved in the leukemogenesis. Importantly, the NPM1 gene mutation is closely asmciated with the FLT3 mutations. In this study we analyzed the molecular mechanism of mutant NPM for the development and progression of leukemia in the association with FLT3 gene mutations and found the following results.1.We established the stably wild type or mutant NPM1-expressing 32D cell lines. Both cell lines did not show the 113 independent growth, and the proliferation rates were same.2.Next we established the FLT3 and NPM1 coexpressing 32D cell lines. Mutant FLT3-expressing 32D cells showed IL3-independent growth, while additional expressing of wild type or mutant NPM1 did not affect the proliferation rate and G-CSF-induced differentiation.3.However, growth inhibitory effects of several anti-leukemia agents and FLT3 kin ace inhibitors were lower in FLT3 and wild type NPM1-caexpressing 32D cells than FLT3 and mutant NPM1-coexpreccing cells.4.Expression level of NPM1 mRNAis lower in the advanced stage MDS cells.5.We generated wild type or mutant NPM specific antibodies. These antibodies can be used both in western blot and immunohistochemistry. By using these antibodies, we found mutant NPM exists in nucleus outside nucleoli as well as cytoplasma

约30%的急性髓性白血病（AMC）患者存在核磷蛋白（NPMI）基因突变，并与完全缓解率和长期生存率密切相关。此外，有报道称NPM1基因的低表达水平可导致骨髓增生异常综合征（MDS）的发生。因此，NPM似乎在AML和MDS的发生和进展中发挥了重要作用。到目前为止，据报道有几种基因改变与白血病的发生有关。重要的是，NPM1基因突变与FLT3突变密切相关。在本研究中，我们分析了突变型NPM与FLT3基因突变相关的白血病发生发展的分子机制，发现如下结果：1。我们建立了稳定的野生型或突变型表达npm1的32D细胞系。两种细胞系均未表现出113独立生长，增殖速率相同。接下来，我们建立了FLT3和NPM1共表达的32D细胞系。突变型flt3表达的32D细胞表现为il3独立生长，而额外表达野生型或突变型NPM1不影响增殖率和g - csf诱导的分化。然而，几种抗白血病药物和FLT3 kin ace抑制剂在FLT3和野生型npm1 - ca表达32D细胞中的生长抑制作用低于FLT3和突变型npm1 - ca表达32D细胞。NPM1 mrna在晚期MDS细胞中的表达水平较低。我们产生了野生型或突变型NPM特异性抗体。这些抗体可用于免疫印迹和免疫组织化学。利用这些抗体，我们发现突变的NPM存在于核仁外的细胞核和细胞质中

项目成果

Disseminated intravascular coagulation in acute leukemia : clinical and laboratory features at pesentation

急性白血病弥散性血管内凝血：临床和实验室特征

• 发表时间: 2006
• 期刊: EurJHaematol 77
• 作者: Yanada;M
• 通讯作者: M

Mutations of N-RAS, FLT3 and p53 genes are not involved in the development of acute leukemia transformed from myelopmliferative diseases with .JAK2 mutation

N-RAS、FLT3和p53基因突变与.JAK2突变骨髓增生性疾病转化的急性白血病的发生无关

• 发表时间: 2006
• 期刊: Leukemia 20
• 作者: Suzuki;M
• 通讯作者: M

Biology, clinical relevance, and moleculary targeted therapy in acute leukemia with FLT3 mutations.

FLT3 突变急性白血病的生物学、临床相关性和分子靶向治疗。

• 发表时间: 2006
• 期刊: Int J Hematol 83
• 作者: Kaman;S;Akihiro Abe;Masamitsu Yanada;Tomoki Naoe;Manabu Ninomiya;Masamitsu Yanada;Hitoshi Kiyoi
• 通讯作者: Hitoshi Kiyoi

Analysis of the Role of Wnt Signaling for the Interaction between Leukemia Cells and Stroma

Wnt 信号转导在白血病细胞与基质相互作用中的作用分析

• 发表时间: 2007
• 作者: Kaman;S;Akihiro Abe;Masamitsu Yanada;Tomoki Naoe;Manabu Ninomiya;Masamitsu Yanada;Hitoshi Kiyoi;Akihide Atsumi;Masamitsu Yanada;Momoko Suzuki;Tomoko Yamamoto;Hitoshi Kiyoi;Sivasundaram Karnan;Yukimasa Shiotsu;Akihiro Tomita;Tomohiko Sato;Toshihiro Iwasaki;Hiroto Narimatsu;Yuichi Ishikawa;Akihiro Abe
• 通讯作者: Akihiro Abe

Randomized Clinical Trial of Induction Therapy Comparing Intensified Daunorubicin with Idarubicin in Patients with Previously Untreated De Novo Acute Myeloid Leukemia(JALSG AML201 Study)

比较强化柔红霉素与伊达比星诱导治疗对既往未经治疗的新发急性髓系白血病患者的随机临床试验（JALSG AML201 研究）

• 发表时间: 2007
• 作者: Kaman;S;Akihiro Abe;Masamitsu Yanada;Tomoki Naoe;Manabu Ninomiya;Masamitsu Yanada;Hitoshi Kiyoi;Akihide Atsumi;Masamitsu Yanada;Momoko Suzuki;Tomoko Yamamoto;Hitoshi Kiyoi;Sivasundaram Karnan;Yukimasa Shiotsu;Akihiro Tomita;Tomohiko Sato;Toshihiro Iwasaki;Hiroto Narimatsu;Yuichi Ishikawa;Akihiro Abe;Fumihiko Hayakawa;Shigeki Ohtake
• 通讯作者: Shigeki Ohtake