RUNX1基因突变在BCR-ABL1阳性白血病中的致病机制及靶向治疗研究

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中文摘要
t(9;22)(q34;q11)/BCR-ABL融合基因在急性白血病(AL)中可见于急性B淋巴细胞白血病(B-ALL)、混合表型急性白血病(MPAL)和急性髓细胞白血病(AML)。在BCR-ABL1共同背景下,导致三类白血病形成迥异临床和分子表型的机制尚未完全明确。申请人前期自5829例AL患者中筛选到351例Ph+B-ALL、26例Ph+MPAL和17例Ph+AML患者,并通过基因芯片和新一代基因测序技术首次发现Ph+MPAL和Ph+AML患者RUNX1基因突变分别高达55%和50%,远高于Ph+B-ALL。提示RUNX1基因突变在Ph+AL的发病和表型形成中发挥关键作用。本课题拟应用模式细胞、条件性敲入小鼠和PDX模型,明确RUNX1突变在Ph+AL中的生物学效应、作用机制和可能的治疗靶点。本课题将为深入理解Ph+AL的发病机制、探索新的靶点治疗策略提供理论和实验依据。
英文摘要
The most frequent cytogenetic abnormality among adults with B-cell acute lymphoblastic leukemia (B-ALL) is the presence of the Philadelphia chromosome (Ph) resulting from t(9;22)(q34;q11), which encodes the BCR-ABL1 fusion gene. It has also been identified in mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML). Currently, the discrepancies between these patients and which cooperating-factors determine the differentiation of the leukemia cells remain undefined. Recently, we identified 351 patients with Ph+ B-ALL, 26 with Ph+ MPAL, and 17 with Ph+ AML by screening 5829 patients with acute leukemia (AL). Moreover, we identified high frequencies of mutations in RUNX1 gene in Ph+ MPAL (55%) and in Ph+ AML (50%) by next-generation sequencing. We thus hypothesize that the co-occurrence of RUNX1 mutation impair the phenotype of leukemia in the mutational background of BCR-ABL1. Therefore, we will explore the co-operation of BCR-ABL1 fusion gene harbored RUNX1 mutation in leukemogenesis through the transfection of 32D or CD34 cells from cord blood. The experiments of proliferation, differentiation and colony forming assays will be performed to confirm the co-operation of BCR-ABL1 fusion gene and RUNX1 mutation in vitro. The genetic mice model and PDX model of BCR-ABL1 and RUNX1 mutation will be further studied from different ways in vivo, such as the latency period, the immunophenotype of organs, the routine analysis of peripheral blood and so on. In terms of treatment, we will further delineate the sensitivity of genetic modified cells and leukemia mice model to small-molecule-inhibitors of RUNX1. This study will provide more details on the pathogenesis and target treatment in Ph-positive leukemia harboring RUNX1 mutations..We plan to determine the role of RUNX1 mutation in leukemia cells with t(9;22)(q34;q11)/BCR-ABL1 using multiple in vivo and in vitro techniques, such as gene transfection, RNA interference, and animal models. This study will provide more details on the pathogenesis and targeted-therapy of AL with t(9;22)(q34;q11)/BCR-ABL1.
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DOI:10.1111/bjh.19233
发表时间:2023-11
期刊:British Journal of Haematology
影响因子:6.5
作者:Qiongyu Lu;Wenqiang Qu;Yuxin Wen;Peng Ke;Luyao Zhao;Qingyuan Wang;Suning Chen;Z. Zeng
通讯作者:Qiongyu Lu;Wenqiang Qu;Yuxin Wen;Peng Ke;Luyao Zhao;Qingyuan Wang;Suning Chen;Z. Zeng
Identification of a novel TNRC18-RARA fusion in acute promyelocytic leukemia lacking t(15;17)(q24;q12)/PML-RARA
缺乏 t(15;17)(q24;q12)/PML-RARA 的急性早幼粒细胞白血病中新型 TNRC18-RARA 融合蛋白的鉴定
DOI:10.1002/mc.23276
发表时间:2021-01-11
期刊:MOLECULAR CARCINOGENESIS
影响因子:4.6
作者:Wang, Zheng;Wen, Lijun;Chen, Suning
通讯作者:Chen, Suning
Identification and validation of a 7-genes prognostic signature for adult acute myeloid leukemia based on aging-related genes.
基于衰老相关基因的成人急性髓系白血病的 7 个基因预后特征的鉴定和验证。
DOI:10.18632/aging.204843
发表时间:2023-06-26
期刊:Aging
影响因子:--
作者:
通讯作者:
DOI:10.1007/s00277-023-05313-3.
发表时间:2023
期刊:Annals of Hematology
影响因子:--
作者:Zhiyou Yu;Yao Yao;Yanming Zhang;Jia Chen;Yang Xu;Shengli Xue;Huiying Qiu;Xiaowen Tang;Yue Han;Suning Chen;Aining Sun;Depei Wu;Ying Wang
通讯作者:Ying Wang
DOI:10.1111/bjh.16294
发表时间:2020
期刊:British Journal of Haematology
影响因子:--
作者:Wang Tingjing;Wang Zheng;Zhang Ling;Wen Lijun;Cai Wenzhi;Yang Xiaofei;Pan Jinlan;Ruan Changgeng;Wu Depei;Sun Aining;Chen Suning
通讯作者:Chen Suning
维甲酸分化综合征的发病机制及靶向治疗研究
- 批准号:82170158
- 项目类别:面上项目
- 资助金额:54万元
- 批准年份:2021
- 负责人:陈苏宁
- 依托单位:
NUP98重排白血病的致病机制研究
- 批准号:81570139
- 项目类别:面上项目
- 资助金额:55.0万元
- 批准年份:2015
- 负责人:陈苏宁
- 依托单位:
t(16;21)(p11;q22)/FUS-ERG融合基因相关急性白血病的生物学特征及发病机制研究
- 批准号:81070416
- 项目类别:面上项目
- 资助金额:35.0万元
- 批准年份:2010
- 负责人:陈苏宁
- 依托单位:
国内基金
海外基金
