The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells
The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells
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DOI：
10.1182/blood.v99.1.15
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发表时间：
2002-01-01
期刊：
影响因子：
20.3
通讯作者：
Nimer, SD
中科院分区：
文献类型：
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作者：
Mulloy, JC;Cammenga, J;Nimer, SD
急性髓性白血病-1 (AML1)-ETO融合蛋白由t细胞产生（8;21），在40%的法、美、英M2亚型aml中发现t细胞。AML1- eto以显性负向方式干扰AML1 （RUNX1, CBFA2）转录因子的功能，并通过结合其一致的dna结合位点和通过与其他转录因子的蛋白-蛋白相互作用来抑制转录。AML1活性对最终造血的发展至关重要，AML1的单倍不足与AML的发展倾向有关。小鼠实验表明AML1-ETO表达可能不足以导致白血病的发生；然而，就像BCR-ABL亚型一样，这些融合蛋白表达的细胞背景可能对观察到的表型至关重要。采用逆转录病毒基因转染方法研究AML1-ETO对人造血干细胞和祖细胞体外行为的影响。CD34（+）细胞转导后，干细胞和祖细胞在克隆测定、细胞因子驱动扩增培养和长期间质共培养中被量化。AML1-ETO的表达抑制了承诺祖细胞的集落形成，但促进了干细胞（鹅卵石区域形成细胞）的生长，导致转导细胞比非转导细胞具有深刻的生存优势。在5周的长期培养过程中，表达ami -1- eto的细胞保留了祖细胞活性，并继续表达CD34。因此，AML1-ETO增强了多能干细胞的自我更新，而多能干细胞是许多急性髓性白血病的生理靶点。
The acute myelogenous leukemia-1 (AML1)-ETO fusion protein is generated by the t(8;21), which is found in 40% of AMLs of the French-American-British M2 subtype. AML1-ETO interferes with the function of the AML1 (RUNX1, CBFA2) transcription factor in a dominant-negative fashion and represses transcription by binding its consensus DNA-binding site and via protein-protein interactions with other transcription factors. AML1 activity is critical for the development of definitive hematopoiesis, and haploinsufficiency of AML1 has been linked to a propensity to develop AML. Murine experiments suggest that AML1-ETO expression may not be sufficient for leukemogenesis; however, like the BCR-ABL isoforms, the cellular background in which these fusion proteins are expressed may be critical to the phenotype observed. Retroviral gene transfer was used to examine the effect of AML1-ETO on the in vitro behavior of human hematopoietic stem and progenitor: cells. Following transduction of CD34(+) cells, stem and progenitor cells were quantified in clonogenic assays, cytokine-driven expansion cultures, and long-term stromal cocultures. Expression of AML1-ETO inhibited colony formation by committed progenitors, but enhanced the growth of stem cells (cobblestone area-forming cells), resulting in a profound survival advantage of transduced over nontransduced cells. AMI-1-ETO-expressing cells retained progenitor activity and continued to express CD34 throughout the 5-week long-term culture. Thus, AML1-ETO enhances the self-renewal of pluripotent stem cells, the physiological target of many acute myeloid leukemias.