MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia.
MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia.
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DOI：
10.1038/onc.2011.208
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发表时间：
2012-01-05
期刊：
影响因子：
8
通讯作者：
Chen, Y-Q
中科院分区：
文献类型：
--
作者：
Zheng, Y-S;Zhang, H.;Zhang, X-J;Feng, D-D;Luo, X-Q;Zeng, C-W;Lin, K-Y;Zhou, H.;Qu, L-H;Zhang, P.;Chen, Y-Q
急性成髓细胞白血病（AML）的特征是异常成髓细胞（主要是粒细胞或单核细胞前体）在骨髓和血液中的积聚。尽管在过去的几十年里，临床治疗取得了很大的进步，但只有少数AML患者获得长期生存。因此，进一步了解白血病的发生机制和探索新的治疗策略仍然是改善疾病预后的关键。MicroRNA-100（miR-100）是一种小的非编码RNA分子，已被报道为AML患者异常表达的常见事件;然而，这种表型的分子基础及其下游靶点的状态尚未阐明。在本研究中，我们发现miR-100在体内的表达水平与髓系白血病亚型的成熟阻滞阶段有关。体外实验进一步证明，需要miR-100来促进早幼粒细胞母细胞的细胞增殖并阻止它们分化为粒细胞/单核细胞谱系。值得注意的是，我们鉴定了RBSP 3，一种磷酸酶样肿瘤抑制因子，作为miR-100的真正靶点，并验证了RBSP 3参与AML的细胞分化和存活。此外，我们揭示了一个新的途径，miR-100调节G1/S转换和S期进入，并通过靶向RBSP 3阻断终末分化，这反过来又部分调节AML中的细胞周期效应子pRB/E2 F1。这些事件促进细胞增殖并阻断粒细胞/单核细胞分化。我们的数据强调了miR-100在AML的分子病因学中的重要作用，并暗示了miR-100在癌症治疗中的潜在应用。
Acute myeloblastic leukemia (AML) is characterized by the accumulation of abnormal myeloblasts (mainly granulocyte or monocyte precursors) in the bone marrow and blood. Though great progress has been made for improvement in clinical treatment during the past decades, only minority with AML achieve long-term survival. Therefore, further understanding mechanisms of leukemogenesis and exploring novel therapeutic strategies are still crucial for improving disease outcome. MicroRNA-100 (miR-100), a small non-coding RNA molecule, has been reported as a frequent event aberrantly expressed in patients with AML; however, the molecular basis for this phenotype and the statuses of its downstream targets have not yet been elucidated. In the present study, we found that the expression level of miR-100 in vivo was related to the stage of the maturation block underlying the subtypes of myeloid leukemia. In vitro experiments further demonstrated that miR-100 was required to promote the cell proliferation of promyelocytic blasts and arrest them differentiated to granulocyte/monocyte lineages. Significantly, we identified RBSP3, a phosphatase-like tumor suppressor, as a bona fide target of miR-100 and validated that RBSP3 was involved in cell differentiation and survival in AML. Moreover, we revealed a new pathway that miR-100 regulates G1/S transition and S-phase entry and blocks the terminal differentiation by targeting RBSP3, which partly in turn modulates the cell cycle effectors pRB/E2F1 in AML. These events promoted cell proliferation and blocked granulocyte/monocyte differentiation. Our data highlight an important role of miR-100 in the molecular etiology of AML, and implicate the potential application of miR-100 in cancer therapy.
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DOI：
10.1084/jem.20090831
发表时间：
2010-03-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Han YC;Park CY;Bhagat G;Zhang J;Wang Y;Fan JB;Liu M;Zou Y;Weissman IL;Gu H
通讯作者：
Gu H
影响因子：
11.2
作者：
Ji, Y;Studzinski, GP
通讯作者：
Studzinski, GP
影响因子：
8
作者：
Lee, K-H;Chen, Y-L;Lu, P-J
通讯作者：
Lu, P-J
DOI：
10.1084/jem.20080285
发表时间：
2008-10-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bousquet M;Quelen C;Rosati R;Mansat-De Mas V;La Starza R;Bastard C;Lippert E;Talmant P;Lafage-Pochitaloff M;Leroux D;Gervais C;Viguié F;Lai JL;Terre C;Beverlo B;Sambani C;Hagemeijer A;Marynen P;Delsol G;Dastugue N;Mecucci C;Brousset P
通讯作者：
Brousset P
影响因子：
5.3
作者：
COLLINS, SJ;ROBERTSON, KA;MUELLER, L
通讯作者：
MUELLER, L