Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma.
Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma.
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DOI：
10.1038/bcj.2014.67
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发表时间：
2014-10-10
影响因子：
12.8
通讯作者：
Chiarle, R.
中科院分区：
文献类型：
--
作者：
Barreca, A.;Martinengo, C.;Annaratone, L.;Righi, L.;Chiappella, A.;Ladetto, M.;Demurtas, A.;Chiusa, L.;Stacchini, A.;Crosetto, N.;van Oudenaarden, A.;Chiarle, R.
大多数滤泡性淋巴瘤（FL）在遗传学上由t（14;18）（q32;q21）易位定义，该易位将BCL 2基因与免疫球蛋白重链（IgH）3'调节区（IgH-3' RR）并列。尽管这种复发性易位，FL病例在获得性突变和肿瘤微环境变化的肿瘤内克隆多样性方面是异质的。在这里，我们描述了一个额外的机制，有助于间和瘤内异质性的FL。通过应用一种新的单分子RNA荧光原位杂交（FISH）技术来检测单个细胞中BCL 2和IgH的mRNA分子，我们发现单个淋巴瘤细胞内BCL 2 mRNA转录物的数量存在显着的异质性。此外，BCL 2 mRNA分子与IgH mRNA分子在t（14;18）淋巴瘤细胞系和患者样本的单个细胞。结论：205例FL患者中BCL 2和IgH蛋白水平呈高度相关性。BCL 2表达的肿瘤间和肿瘤内异质性决定了FL治疗中常用药物的耐药性，并影响FL患者的总生存率。这些数据表明，BCL 2和IgH的表达是异质性的，并在t（14;18）-易位的细胞中共同调节，并决定FL患者对治疗的反应。
Most follicular lymphomas (FLs) are genetically defined by the t(14;18)(q32;q21) translocation that juxtaposes the BCL2 gene to the immunoglobulin heavy chain (IgH) 3' regulatory regions (IgH-3'RRs). Despite this recurrent translocation, FL cases are heterogeneous in terms of intratumoral clonal diversity for acquired mutations and variations in the tumor microenvironment. Here we describe an additional mechanism that contributes to inter- and intratumoral heterogeneity in FLs. By applying a novel single-molecule RNA fluorescence-based in situ hybridization (FISH) technique to detect mRNA molecules of BCL2 and IgH in single cells, we found marked heterogeneity in the number of BCL2 mRNA transcripts within individual lymphoma cells. Moreover, BCL2 mRNA molecules correlated with IgH mRNA molecules in individual cells both in t(14;18) lymphoma cell lines and in patient samples. Consistently, a strong correlation between BCL2 and IgH protein levels was found in a series of 205 primary FL cases by flow cytometry and immunohistochemistry. Inter- and intratumoral heterogeneity of BCL2 expression determined resistance to drugs commonly used in FL treatment and affected overall survival of FL patients. These data demonstrate that BCL2 and IgH expressions are heterogeneous and coregulated in t(14;18)-translocated cells, and determine the response to therapy in FL patients.
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影响因子：
3.6
作者：
Klapper, Wolfram
通讯作者：
Klapper, Wolfram
影响因子：
3.4
作者：
Demurtas, Anna;Stacchini, Alessandra;Novero, Domenico
通讯作者：
Novero, Domenico
在人卵泡淋巴瘤中检测第二t（14; 18）断点簇区域。
影响因子：
15.3
作者：
Cleary, M L;Galili, N;Sklar, J
通讯作者：
Sklar, J
影响因子：
20.3
作者：
Green, Michael R.;Gentles, Andrew J.;Alizadeh, Ash A.
通讯作者：
Alizadeh, Ash A.
影响因子：
4.4
作者：
Gordon, SJ;Saeque, S;Birshtein, BK
通讯作者：
Birshtein, BK