MAPK and JAK-STAT pathways dysregulation in plasmablastic lymphoma.
MAPK and JAK-STAT pathways dysregulation in plasmablastic lymphoma.
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DOI：
10.3324/haematol.2020.271957
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发表时间：
2021-10-01
期刊：
影响因子：
10.1
通讯作者：
Campo E
中科院分区：
文献类型：
--
作者：
Ramis-Zaldivar JE;Gonzalez-Farre B;Nicolae A;Pack S;Clot G;Nadeu F;Mottok A;Horn H;Song JY;Fu K;Wright G;Gascoyne RD;Chan WC;Scott DW;Feldman AL;Valera A;Enjuanes A;Braziel RM;Smeland EB;Staudt LM;Rosenwald A;Rimsza LM;Ott G;Jaffe ES;Salaverria I;Campo E
浆母细胞淋巴瘤 (PBL) 是一种侵袭性 B 细胞淋巴瘤，具有免疫母细胞/大细胞形态和终末 B 细胞分化。由于形态学、遗传和免疫表型特征重叠，与伯基特淋巴瘤、浆细胞骨髓瘤和弥漫性大 B 细胞淋巴瘤的某些变体的鉴别诊断可能具有挑战性。此外，PBL 中的基因组景观尚不清楚。为了表征这些肿瘤的遗传和分子异质性，我们使用综合方法研究了 34 例 PBL 病例，包括荧光原位杂交、94 个 B 细胞淋巴瘤相关基因的靶向测序和拷贝数阵列。 PBL 的特点是遗传复杂性高，包括 MYC 易位 (87%)、1q21.1-q44、7 三体、8q23.2-q24.21、11p13-p11.2、11q14.2-q25、12p 和 19p13.3-p13.13 的增加、1p33 的损失、 1p31.1-p22.3、13q 和 17p13.3-p11.2，以及 STAT3 (37%)、NRAS 和 TP53 (33%)、MYC 和 EP300 (19%) 以及 CARD11、SOCS1 和 TET2 (11%) 的复发突变。通路富集分析表明 MYC 改变与 MAPK (49%) 和 JAK-STAT (40%) 信号通路之间存在协同作用。值得注意的是，EB 病毒 (EBV) 阴性 PBL 病例具有更高的突变和拷贝数负载以及更频繁的 TP53、CARD11 和 MYC 突变，而 EBV 阳性 PBL 往往有更多影响 JAK-STAT 通路的突变。总之，这些发现进一步揭示了 PBL 识别新分子靶标的独特分子异质性以及这些肿瘤与 EBV 感染相关的不同遗传特征。
Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma with an immunoblastic/large-cell morphology and terminal B-cell differentiation. The differential diagnosis from Burkitt lymphoma, plasma cell myeloma and some variants of diffuse large B-cell lymphoma may be challenging because of the overlapping morphological, genetic and immunophenotypic features. Furthermore, the genomic landscape in PBL is not well known. To characterize the genetic and molecular heterogeneity of these tumors, we investigated 34 cases of PBL using an integrated approach, including fluorescence in situ hybridization, targeted sequencing of 94 B-cell lymphoma-related genes, and copy-number arrays. PBL were characterized by high genetic complexity including MYC translocations (87%), gains of 1q21.1-q44, trisomy 7, 8q23.2- q24.21, 11p13-p11.2, 11q14.2-q25, 12p and 19p13.3-p13.13, losses of 1p33, 1p31.1-p22.3, 13q and 17p13.3-p11.2, and recurrent mutations of STAT3 (37%), NRAS and TP53 (33%), MYC and EP300 (19%) and CARD11, SOCS1 and TET2 (11%). Pathway enrichment analysis suggested a cooperative action between MYC alterations and MAPK (49%) and JAK-STAT (40%) signaling pathways. Of note, Epstein-Barr virus (EBV)-negative PBL cases had higher mutational and copy-number load and more frequent TP53, CARD11 and MYC mutations, whereas EBVpositive PBL tended to have more mutations affecting the JAK-STAT pathway. In conclusion, these findings further unravel the distinctive molecular heterogeneity of PBL identifying novel molecular targets and the different genetic profile of these tumors in relation to EBV infection.