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Sci Signal:加剧急性髓性白血病恶性程度的真正基因

  1. miR-3151
  2. 基因
  3. 急性髓性白血病

来源:生物谷 2014-04-23 13:14

根据俄亥俄州立大学综合癌症中心-Arthur G. James肿瘤医院和Richard J. Solove研究所研究员一项新的研究证实:一个嵌入在一个较大基因的小基因,才是白血病真的推动力量。

2014年4月22日讯 /生物谷BIOON/--根据俄亥俄州立大学综合癌症中心-Arthur G. James肿瘤医院和Richard J. Solove研究所研究员一项新的研究证实:一个嵌入在一个较大基因(知名的基因)的小基因,才是白血病真的推动力量。

该研究结果发表在杂志Science Signaling上。较大的宿主基因被称为BAALC,较小的嵌入式基因被称为微RNA-3151(miR-3151)。该研究调查了每个基因对急性髓性白血病(AML)发展的贡献程度。

首席研究员Albert de la Chapelle博士表示:我们发现,小分子RNA基因,而不是更大的宿主基因,是AML的主要致癌驱动基因。当两个基因高表达,它意味着患者预后不良,但我们的实验表明miR-3151的高表达是真正重要的,BAALC单独的过表达只有有限的致癌活性。

研究人员发现了miR-3151通过阻断TP53基因促进白血病的发展。通常情况下,TP53是关键性“肿瘤抑制”基因,TP53通过造成严重受损基因自毁来防癌。当miR-3151阻断肿瘤细胞中TP53,它使细胞存活,分化,生长较快。

研究还显示miR-3151以同样的方式促进恶性黑色素瘤细胞的增长,这表明该分子可能在实体肿瘤的发展起到一定的作用。最后,研究人员证明药物硼替佐米(蛋白酶体抑制剂)能抑制miR-3151的过表达。(生物谷Bioon.com)

 

Intronic miR-3151 Within BAALC Drives Leukemogenesis by Deregulating the TP53 Pathway

Ann-Kathrin Eisfeld, Sebastian Schwind, Ravi Patel, Xiaomeng Huang, Ramasamy Santhanam, Christopher J. Walker, Joseph Markowitz, Kevin W. Hoag, Tiina M. Jarvinen, Benjamin Leffel, Danilo Perrotti, William E. Carson III, Guido Marcucci, Clara D. Bloomfield*, and Albert de la Chapelle*

Abstract: The BAALC/miR-3151 locus on chromosome 8q22 contains both the BAALC gene (for brain and acute leukemia, cytoplasmic) and miR-3151, which is located in intron 1 of BAALC. Older acute myeloid leukemia (AML) patients with high expression of both miR-3151 and the BAALC mRNA transcript have a low survival prognosis, and miR-3151 and BAALC expression is associated with poor survival independently of each other. We found that miR-3151 functioned as the oncogenic driver of the BAALC/miR-3151 locus. Increased production of miR-3151 reduced the apoptosis and chemosensitivity of AML cell lines and increased leukemogenesis in mice. Disruption of the TP53-mediated apoptosis pathway occurred in leukemia cells overexpressing miR-3151 and the miR-3151 bound to the 3' untranslated region of TP53. In contrast, BAALC alone had only limited oncogenic activity. We found that miR-3151 contains its own regulatory element, thus partly uncoupling miR-3151 expression from that of the BAALC transcript. Both genes were bound and stimulated by a complex of the transcription factors SP1 and nuclear factor B (SP1/NF-B). Disruption of SP1/NF-B binding reduced both miR-3151 and BAALC expression. However, expression of only BAALC, but not miR-3151, was stimulated by the transcription factor RUNX1, suggesting a mechanism for the partly discordant expression of miR-3151 and BAALC observed in AML patients. Similar to the AML cells, in melanoma cell lines, overexpression of miR-3151 reduced the abundance of TP53, and knockdown of miR-3151 increased caspase activity, whereas miR-3151 overexpression reduced caspase activity. Thus, this oncogenic miR-3151 may also have a role in solid tumors.

 

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