Deregulated E2F-1 blocks terminal differentiation and loss of leukemogenicity of M1 myeloblastic leukemia cells without abrogating induction of p15(INK4B) and p16(INK4A).
Deregulated E2F-1 blocks terminal differentiation and loss of leukemogenicity of M1 myeloblastic leukemia cells without abrogating induction of p15(INK4B) and p16(INK4A).
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DOI：
10.1182/blood.v96.2.475.014k38_475_482
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发表时间：
2000
期刊：
影响因子：
20.3
通讯作者：
A. Amanullah;B. Hoffman;D. Liebermann
中科院分区：
文献类型：
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作者：
A. Amanullah;B. Hoffman;D. Liebermann
转录因子E2 F-1被认为在控制细胞周期进程中起着至关重要的作用，因为它能够被视网膜母细胞瘤基因产物（pRb）结合和调节。在生长限制性条件下，E2 F-1的外源性表达显示导致p53依赖性程序性细胞死亡。在E2 F-1介导的细胞凋亡不存在的情况下，E2 F-1表达失调对造血细胞终末分化的影响，以及E2 F-1失调如何影响终末分化的机制见解尚未建立。自主增殖的M1成髓细胞白血病细胞系，这是空的p53表达，并可以诱导白细胞介素-6（IL-6）进行终末巨噬细胞分化伴随着白血病的损失，提供了一个特别有吸引力的模型系统，以解决这些问题。E2 F-1的去调节和持续表达在早期胚细胞阶段阻断了IL-6诱导的终末分化程序，产生未成熟细胞，这些细胞继续增殖而不发生细胞凋亡，并保留其致白血病表型。虽然E2 F-1阻断了IL-6介导的终末分化及其相关的生长停滞，但它不能阻止p15（INK 4 B）和p16（INK 4A）的快速诱导、cdk 4激酶活性的抑制以及随后的pRb低磷酸化。所获得的结果意味着，既损害p53功能和失调E2 F-1表达的遗传改变可能会使造血细胞分化诱导难治性，从而可能在白血病的进展中发挥重要作用。（血。2000;96：475-482）
The transcription factor E2F-1 has been postulated to play a crucial role in the control of cell cycle progression because of its ability to be bound and regulated by the retinoblastoma gene product (pRb). Exogenous expression of E2F-1, under growth restrictive conditions, was shown to result in p53-dependent programmed cell death. The consequences of deregulated expression of E2F-1 on terminal differentiation of hematopoietic cells in the absence of E2F-1-mediated apoptosis, as well as mechanistic insights into how deregulated E2F-1 may affect terminal differentiation, have not been established. The autonomously proliferating M1 myeloblastic leukemia cell line, which is null for p53 expression and can be induced by interleukin-6 (IL-6) to undergo terminal macrophage differentiation with concomitant loss of leukemogenicity, provides a particularly attractive model system to address these issues. Deregulated and continued expression of E2F-1 blocked the IL-6-induced terminal differentiation program at an early blast stage, giving rise to immature cells, which continued to proliferate without undergoing apoptosis and retained their leukemogenic phenotype. Although E2F-1 blocked IL-6-mediated terminal differentiation and its associated growth arrest, it did not prevent the rapid induction of both p15(INK4B) and p16(INK4A), inhibition of cdk4 kinase activity, and subsequent hypophosphorylation of pRb. The results obtained imply that genetic alterations that both impair p53 function and deregulate E2F-1 expression may render hematopoietic cells refractory to the induction of differentiation and are, thereby, likely to play a major role in the progression of leukemias. (Blood. 2000;96:475-482)