MEF2B Instructs Germinal Center Development and Acts as an Oncogene in B Cell Lymphomagenesis.
MEF2B Instructs Germinal Center Development and Acts as an Oncogene in B Cell Lymphomagenesis.
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DOI：
10.1016/j.ccell.2018.08.006
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发表时间：
2018-09-10
期刊：
影响因子：
50.3
通讯作者：
Dalla-Favera R
中科院分区：
文献类型：
--
作者：
Brescia P;Schneider C;Holmes AB;Shen Q;Hussein S;Pasqualucci L;Basso K;Dalla-Favera R
编码MEF2B转录因子的基因在生殖中心（GC）衍生的B细胞淋巴瘤中发生突变，但其在GC发展和淋巴瘤发生中的作用尚不清楚。我们证明了Mef2b缺失减少了小鼠中GC的形成，并确定了GC中的MEF2B转录靶点，在细胞增殖、凋亡、GC限制和分化中发挥作用。最常见的淋巴瘤相关MEF2B突变体（MEF2BD83V）是亚型的，但逃脱了HUCA复合物和IIa类HDAC组分的结合和负调控。Mef2bD83V在小鼠中的表达导致GC增大和淋巴瘤发展，这是一种与BCL 2失调组合而变得完全外显的表型，这是与人MEF2B突变相关的事件。这些结果确定MEF2B作为一个关键的GC调节和驱动癌基因在淋巴瘤发生。MEF 2 B在约15%的滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤中突变，这是成熟B细胞恶性肿瘤的最常见类型。在这里，我们建立了一个关键的生理作用MEF 2 B在GC B细胞的发展，细胞的起源，大多数人B细胞淋巴瘤。通过对小鼠中最常见的淋巴瘤相关MEF2B突变等位基因的表达进行建模，我们证明了突变MEF2B有助于体内淋巴瘤的发生，并确定了相关的生化机制。MEF2B突变体驱动的小鼠淋巴瘤代表了用于临床前治疗测试的人类疾病的可靠模型。Brescia等表明MEF 2 B对于生发中心（GC）形成至关重要，并鉴定了GC B细胞中的MEF 2 B转录靶标。他们还表征了最常见的淋巴瘤相关MEF2B突变体（MEF2BD83V），并证明MEF2BD83V导致小鼠GC增大和淋巴瘤发展。
The gene encoding the MEF2B transcription factor is mutated in germinal-center (GC)-derived B-cell lymphomas, but its role in GC development and lymphomagenesis is unknown. We demonstrate that Mef2b deletion reduces GC formation in mice and identify MEF2B transcriptional targets in GC, with roles in cell proliferation, apoptosis, GC confinement and differentiation. The most common lymphoma-associated MEF2B mutant (MEF2BD83V) is hypomorphic, yet escapes binding and negative regulation by components of the HUCA complex and class IIa HDACs. Mef2bD83V expression in mice leads to GC enlargement and lymphoma development, a phenotype that becomes fully penetrant in combination with BCL2 de-regulation, an event associated with human MEF2B mutations. These results identify MEF2B as a critical GC regulator and a driver oncogene in lymphomagenesis. MEF2B is mutated in ~15% of Follicular Lymphoma and Diffuse Large B cell Lymphoma, the most common types of mature B cell malignancies. Here we establish a critical physiologic role of MEF2B in the development of GC B cells, the cell-of-origin of most human B cell lymphomas. Modeling the expression of the most frequent lymphoma-associated MEF2B mutant allele in mice, we demonstrate that mutant MEF2B contributes to lymphomagenesis in vivo and identify the involved biochemical mechanism. MEF2B mutant-driven mouse lymphomas represent a faithful model of the human disease for pre-clinical therapeutic testing. Brescia et al. show that MEF2B is critical for germinal center (GC) formation and identify MEF2B transcriptional targets in GC B cells. They also characterize the most common lymphoma-associated MEF2B mutant (MEF2BD83V) and demonstrate that MEF2BD83V leads to GC enlargement and lymphoma development in mice.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
Adams, Peter D.
影响因子：
4.8
作者：
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通讯作者：
Verdin, E
影响因子：
14.8
作者：
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Amit, Ido