Regulation of JAK2 by miR-135a: prognostic impact in classic Hodgkin lymphoma
Regulation of JAK2 by miR-135a: prognostic impact in classic Hodgkin lymphoma
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DOI：
10.1182/blood-2009-02-204842
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发表时间：
2009-10-01
期刊：
影响因子：
20.3
通讯作者：
Monzo, Mariano
中科院分区：
文献类型：
--
作者：
Navarro, Alfons;Diaz, Tania;Monzo, Mariano
经典霍奇金淋巴瘤(CHL)的行为由肿瘤细胞的内在特征和微环境的特征决定，因此对整个淋巴结的分析是了解该病的有效途径。我们研究了我们先前报道的CHL的25-microRNA标记对89名接受同种治疗的CHL患者的临床结果的影响，平均随访时间为80个月。MiR-135a低表达患者的复发几率较高(P=0.04)，无病生存期较短(P=0.02)。对CHL细胞的功能分析表明，前miR-135a转染后成熟miR-135a水平升高，导致细胞凋亡，细胞生长受阻。靶向分析显示，miR-135a直接调节JAK2，一种参与细胞因子受体信号通路特定子集的细胞质酪氨酸激酶。MIR-135修饰的JAK2下调导致抗凋亡基因Bclxl的mRNA和蛋白水平降低，提示Bclxl在miR-135a/JAK2介导的细胞凋亡中发挥作用。我们的发现证实了miR-135a在慢性淋巴细胞白血病细胞存活和患者预后中的关键作用，表明针对miR-135a的新的治疗方法可能会使这些患者受益。(血。2009；114：2945-2951)
The behavior of classic Hodgkin lymphoma (cHL) is determined by both the intrinsic features of the tumor cells and the characteristics of the microenvironment, making the analysis of entire lymph nodes an effective approach to understanding the disease. We examined the influence of our previously reported 25-microRNA signature for cHL on clinical outcome in 89 homogeneously treated cHL patients with a median follow-up of 80 months. Patients with low miR-135a expression had a higher probability of relapse (P=.04) and a shorter disease-free survival (P=.02). Functional analysis of cHL cell lines showed that mature miR-135a levels increased after pre-miR-135a transfection, causing apoptosis and decreased cell growth. Target analysis showed a direct regulation by miR-135a of JAK2, a cytoplasmic tyrosine kinase involved in a specific subset of cytokine receptor signaling pathways. miR-135-amediated JAK2 down-regulation led to decreased mRNA and protein levels of the antiapoptotic gene Bcl-xL, suggesting a role for Bcl-xL in miR-135a/JAK2-mediated apoptosis. Our findings confirm the critical role of miR-135a in the survival of cHL cells and in the prognosis of cHL patients, indicating that novel treatment approaches targeting miR-135a may potentially benefit these patients. (Blood. 2009; 114: 2945-2951)