Plasmablastic lymphoma phenotype is determined by genetic alterations in MYC and PRDM1
Plasmablastic lymphoma phenotype is determined by genetic alterations in MYC and PRDM1
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DOI：
10.1038/modpathol.2016.162
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发表时间：
2017-01-01
期刊：
影响因子：
7.5
通讯作者：
Piris, Miguel A.
中科院分区：
文献类型：
--
作者：
Montes-Moreno, Santiago;Martinez-Magunacelaya, Nerea;Piris, Miguel A.
浆母细胞淋巴瘤是一种罕见的侵袭性非霍奇金B细胞淋巴瘤类型，定义为具有浆细胞表型的高级别大B细胞肿瘤。MYC的遗传改变已在一定比例（约60%）的浆母细胞性淋巴瘤病例中发现，并导致MYC蛋白过表达。在这里，我们对36例浆母细胞瘤淋巴瘤病例进行了遗传和表达谱分析，并证明MYC过表达并不局限于MYC易位（46%）或MYC扩增病例（11%）。此外，我们证明PRDM 1的复发性体细胞突变在50%的浆母细胞淋巴瘤病例中被发现（16例评估中有8例）。这些突变靶向参与不同靶点（如MYC）调节的关键功能结构域（PR基序、富含脯氨酸的结构域、酸性区域和DNA结合锌指结构域）。此外，发现这些突变经常与MYC易位相关（9例中有5例，56%的MYC易位病例是PROM突变的），但不限于这些病例，并导致PRDM 1/Blimpla蛋白表达受损。我们的数据表明，PRDM 1基因突变在浆母细胞淋巴瘤不损害终端B细胞分化，但有助于MYC的致癌性，通常由MYC易位或MYC扩增失调。总之，MYC和PRDM 1/Blimp 1a的异常共表达是由于遗传变化导致的浆母细胞性淋巴瘤病例的表型。
Plasmablastic lymphoma is an uncommon aggressive non-Hodgkin B-cell lymphoma type defined as a high-grade large B-cell neoplasm with plasma cell phenotype. Genetic alterations in MYC have been found in a proportion (similar to 60%) of plasmablastic lymphoma cases and lead to MYC-protein overexpression. Here, we performed a genetic and expression profile of 36 plasmablastic lymphoma cases and demonstrate that MYC overexpression is not restricted to MYC-translocated (46%) or MYC-amplified cases (11%). Furthermore, we demonstrate that recurrent somatic mutations in PRDM1 are found in 50% of plasmablastic lymphoma cases (8 of 16 cases evaluated). These mutations target critical functional domains (PR motif, proline rich domain, acidic region, and DNA-binding Zn-finger domain) involved in the regulation of different targets such as MYC. Furthermore, these mutations are found frequently in association with MYC translocations (5 out of 9, 56% of cases with MYC translocations were PROM-mutated), but not restricted to those cases, and lead to expression of an impaired PRDM1/Blimpla protein. Our data suggest that PRDM1 mutations in plasmablastic lymphoma do not impair terminal B-cell differentiation, but contribute to the oncogenicity of MYC, usually disregulated by MYC translocation or MYC amplification. In conclusion, aberrant coexpression of MYC and PRDM1/Blimp1a owing to genetic changes is responsible for the phenotype of plasmablastic lymphoma cases.