Background

The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping “cell-of-origin”. Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry.

Methods

We compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naïve and memory B-cells) from 36 donor tonsils using >325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and genome copy number (microarrays).

Findings

From the resulting data, we identified gains in active chromatin in enhancers/super-enhancers that likely promote unchecked B-cell receptor signaling, including one we validated near the immunoglobulin superfamily receptors FCMR and PIGR. More striking and pervasive was the profound loss of key B-cell identity TFs, tumor suppressors and their super-enhancers, including EBF1, OCT2(POU2F2), and RUNX3. Using a novel approach to identify transcriptional feedback, we showed that these core transcriptional circuitries are self-regulating. Their selective gain and loss form a complex, iterative, and interactive process that likely curbs B-cell maturation and spurs proliferation.

Interpretation

Our study is the first to map the transcriptional circuitry of the most common blood cancers. We demonstrate that a critical subset of B-cell TFs and their cognate enhancers form self-regulatory transcriptional feedback loops whose disruption is a shared mechanism underlying these diverse subtypes of B-cell lymphoma.

Funding

National Institute of Health, Siteman Cancer Center, Barnes-Jewish Hospital Foundation, Doris Duke Foundation.

中文翻译：

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协同转录反馈环的缺失导致多种 B 细胞癌

背景

最常见的 B 细胞癌、慢性淋巴细胞白血病/淋巴瘤 (CLL)、滤泡性和弥漫性大 B 细胞 (FL、DLBCL) 淋巴瘤具有不同的临床过程，但“起源细胞”却重叠。表观基因组的动态变化是 B 细胞分化的重要调节因子。因此，我们推断这些不同的癌症可能是由转录电路中断的共同机制驱动的。

方法

我们使用 >325 组蛋白修饰、开放染色质的高分辨率分子谱分析，比较了来自 36 个供体扁桃体的 52 名具有正常 B 细胞亚群（生发中心中心细胞和中心母细胞、幼稚和记忆 B 细胞）的患者的纯化恶性 B 细胞。 ChIP-、FAIRE-seq)、转录组 (RNA-seq)、转录因子 (TF) 结合和基因组拷贝数（微阵列）。

发现

从所得数据中，我们确定了增强剂/超级增强剂中活性染色质的增加，这可能促进不受控制的 B 细胞受体信号传导，包括我们在免疫球蛋白超家族受体FCMR和PIGR附近验证的一种。更引人注目和普遍的是关键 B 细胞身份 TF、肿瘤抑制因子及其超级增强子（包括EBF1、OCT2 ( POU2F2 ) 和RUNX3 ）的严重丧失。使用一种新的方法来识别转录反馈，我们发现这些核心转录电路是自我调节的。它们的选择性得失形成了一个复杂的、迭代的和交互的过程，可能会抑制 B 细胞成熟并刺激增殖。

解释

我们的研究首次绘制了最常见血癌的转录电路图。我们证明了 B 细胞 TF 的一个关键子集及其同源增强子形成自我调节转录反馈环，其破坏是这些不同 B 细胞淋巴瘤亚型的共同机制。

资金

美国国立卫生研究院、Siteman 癌症中心、Barnes-Jewish 医院基金会、Doris Duke 基金会。