PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma
PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma
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DOI：
10.1073/pnas.1305656110
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发表时间：
2013-07-23
影响因子：
11.1
通讯作者：
Lenz, Georg
中科院分区：
文献类型：
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作者：
Pfeifer, Matthias;Grau, Michael;Lenz, Georg
弥漫性大B细胞淋巴瘤(DLBCL)是一种异质性诊断类型，具有不同的分子亚型，可以通过基因表达谱来定义。然而，即使在这些已定义的子类型中，异质性仍然占上风。为了进一步阐明这些实体的发病机制，我们检测了248例DLBCL患者标本中肿瘤抑制因子磷酸酶和张力蛋白同源物(PTEN)的表达。这些分析表明，在55%的生发中心B细胞样(GCB)DLBCL中可以检测到PTEN的缺失，而在非GCB DLBCL患者中只有14%的患者存在这种异常。在GCB DLBCL中，PTEN状态与DLBCL细胞系和原发患者样本中致癌PI3K/蛋白激酶B(AKT)通路的激活呈负相关。PTEN的重新表达通过抑制PI3K/AKT信号通路在缺失PTEN的GCB DLBCL细胞模型中诱导细胞毒作用，表明在GCB DLBCL的这一亚群中对这一途径上瘾。PI3K/AKT抑制导致转录因子MYC表达下调。MYC的重新表达使GCB DLBCL细胞免于PTEN诱导的毒性，证实了MYC在DLBCL中表达的调节机制。最后，药物抑制PI3K对PTEN缺失的GCB DLBCL细胞有选择性的毒性作用。总之，我们的结果表明，PTEN缺失定义了一种依赖于PI3K/AKT的GCB DLBCL亚型，该亚型依赖于PI3K和MYC信号，并提示对PI3K的药物抑制可能是这些淋巴瘤的一种有前途的治疗方法。
Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous diagnostic category with distinct molecular subtypes that can be defined by gene expression profiling. However, even within these defined subtypes, heterogeneity prevails. To further elucidate the pathogenesis of these entities, we determined the expression of the tumor suppressor phosphatase and tensin homolog (PTEN) in 248 primary DLBCL patient samples. These analyses revealed that loss of PTEN was detectable in 55% of germinal center B-cell-like (GCB) DLBCLs, whereas this abnormality was found in only 14% of non-GCB DLBCL patient samples. In GCB DLBCL, the PTEN status was inversely correlated with activation of the oncogenic PI3K/protein kinase B (AKT) pathway in both DLBCL cell lines and primary patient samples. Reexpression of PTEN induced cytotoxicity in PTEN-deficient GCB DLBCL cell line models by inhibiting PI3K/AKT signaling, indicating an addiction to this pathway in this subset of GCB DLBCLs. PI3K/AKT inhibition induced down-regulation of the transcription factor MYC. Reexpression of MYC rescued GCB DLBCL cells from PTEN-induced toxicity, identifying a regulatory mechanism of MYC expression in DLBCL. Finally, pharmacologic PI3K inhibition resulted in toxicity selectively in PTEN-deficient GCB DLBCL lines. Collectively, our results indicate that PTEN loss defines a PI3K/AKT-dependent GCB DLBCL subtype that is addicted to PI3K and MYC signaling and suggest that pharmacologic inhibition of PI3K might represent a promising therapeutic approach in these lymphomas.