miRNA let-7c promotes granulocytic differentiation in acute myeloid leukemia.
miRNA let-7c promotes granulocytic differentiation in acute myeloid leukemia.
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DOI：
10.1038/onc.2012.398
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发表时间：
2013-08-01
期刊：
影响因子：
8
通讯作者：
Rizzo MG
中科院分区：
文献类型：
--
作者：
Pelosi A;Careccia S;Lulli V;Romania P;Marziali G;Testa U;Lavorgna S;Lo-Coco F;Petti MC;Calabretta B;Levrero M;Piaggio G;Rizzo MG
MicroRNAs(MiRNAs)是一种小的非编码RNA，在转录后调节基因的表达，参与许多复杂的细胞过程。一些miRNAs在造血组织中有不同的表达，在正常分化中发挥重要作用，但当调节异常时，会导致白血病细胞的异常增殖和分化。最近，我们报道了一小部分miRNAs在急性早幼粒细胞白血病(APL)细胞中差异表达，并受到全反式维甲酸(ATRA)治疗的调节。特别是，来自急性早幼粒细胞白血病患者的PML/RARα阳性原始细胞显示出比正常早幼粒细胞低水平的miRNA let-7c，它是let-7家族的成员之一，经全反式维甲酸治疗后其表达增加。在本研究中，我们研究了let-7c对急性髓系白血病(AML)细胞的作用。我们发现异位表达let-7c促进了AML细胞系和原代母细胞的粒细胞分化。此外，我们发现PBX2是一个新的let-7c靶点，可能与AML表型有关。PBX2是一种众所周知的同源结构域蛋白，其异常表达促进了HoxA9依赖的白血病的发生。总之，这些研究提出了一种可能性，即let-7c-PBX2通路的扰动可能对AML具有治疗价值。
MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression post-transcriptionally, are involved in many complex cellular processes. Several miRNAs are differentially expressed in hematopoietic tissues and play important roles in normal differentiation, but, when aberrantly regulated, contribute to the abnormal proliferation and differentiation of leukemic cells. Recently, we reported that a small subset of miRNAs is differentially expressed in acute promyelocytic leukemia (APL) blasts and is modulated by treatment with all-trans-retinoic acid (ATRA). In particular, PML/RARα-positive blasts from APL patients display lower levels of miRNA let-7c, a member of the let-7 family, than normal promyelocytes and its expression increases after ATRA treatment. In this study, we investigated the effects of let-7c in acute myeloid leukaemia (AML) cells. We found that ectopic expression of let-7c promotes granulocytic differentiation of AML cell lines and primary blasts. Moreover, we identified PBX2, a well-known homeodomain protein whose aberrant expression enhances HoxA9-dependent leukemogenesis, as a novel let-7c target that may contribute to the AML phenotype. Together, these studies raise the possibility that perturbation of the let-7c-PBX2 pathway may have a therapeutic value in AML.
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