The B cell antigen receptor and overexpression of MYC can cooperate in the genesis of B cell lymphomas.
The B cell antigen receptor and overexpression of MYC can cooperate in the genesis of B cell lymphomas.
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DOI：
10.1371/journal.pbio.0060152
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发表时间：
2008-06-24
期刊：
影响因子：
9.8
通讯作者：
Bishop, J. Michael
中科院分区：
文献类型：
--
作者：
Refaeli, Yosef;Young, Ryan M.;Turner, Brian C.;Duda, Jennifer;Field, Kenneth A.;Bishop, J. Michael
来自人类的各种间接证据表明B细胞抗原受体（BCR）参与B细胞淋巴瘤的发生。我们建立了小鼠模型，旨在直接测试这种可能性，我们发现克隆BCR的组成和抗原刺激状态都会影响原癌基因MYC引发的淋巴瘤发生的速率和结果。在存在组成性BCR的情况下产生的肿瘤不同于单独由MYC引发的肿瘤，并且类似于慢性B细胞淋巴细胞白血病/淋巴瘤（B-CLL），而那些响应于抗原刺激而产生的肿瘤类似于大B细胞淋巴瘤，特别是伯基特淋巴瘤（BL）。我们将BL样肿瘤的发生与抗原刺激以三种方式联系起来。首先，在重建实验中，在存在过表达的MYC的情况下，自身抗原刺激B细胞产生BL样肿瘤，BL样肿瘤反过来依赖于MYC和抗原的存活和增殖。其次，介导BCR信号传导的通路的遗传破坏迅速杀死BL样肿瘤以及类似B-CLL的肿瘤的细胞。第三，小鼠BL的生长可以被三种不同的免疫抑制剂中的任何一种抑制，这与肿瘤对抗原诱导的信号传导的依赖性雅阁。总之，我们的研究结果提供了直接的证据表明，抗原刺激可以参与淋巴瘤的发生，指出一个潜在的作用，以及组成型BCR，并支持的观点，组成型BCR引起的信号不同于抗原引起的。这里描述的小鼠模型应该是有用的，在进一步探索淋巴瘤的发病机制，并在临床前测试的新疗法。长期以来，人们一直怀疑，被称为淋巴瘤的B淋巴细胞的恶性增殖可能代表了细胞对抗原的正常反应的反常。特别是，细胞表面的分子受体，信号的抗原的存在可能是异常活跃的淋巴瘤。我们已经通过改造小鼠的基因组来验证这一假设，这样几乎所有的B细胞都被一种单一的表面受体占据，然后用它被设计来识别的分子刺激该受体。我们的研究结果表明，无论是未受刺激和刺激状态的受体可以合作与癌基因称为MYC在淋巴瘤的发生。但是受体的两种状态引起不同形式的淋巴瘤。特别是，刺激形式与MYC合作产生一种与伯基特淋巴瘤非常相似的疾病。这些结果阐明了导致淋巴瘤的机制，并可能为治疗该疾病的新策略的发展提供信息。一系列的基因工程小鼠被用来证实一个长期的推测，慢性免疫刺激可能参与某些淋巴瘤的发生，阐明了B细胞淋巴瘤的发病机制，并提出了新的策略来治疗这种恶性肿瘤的几种形式，包括伯基特淋巴瘤。
A variety of circumstantial evidence from humans has implicated the B cell antigen receptor (BCR) in the genesis of B cell lymphomas. We generated mouse models designed to test this possibility directly, and we found that both the constitutive and antigen-stimulated state of a clonal BCR affected the rate and outcome of lymphomagenesis initiated by the proto-oncogene MYC. The tumors that arose in the presence of constitutive BCR differed from those initiated by MYC alone and resembled chronic B cell lymphocytic leukemia/lymphoma (B-CLL), whereas those that arose in response to antigen stimulation resembled large B-cell lymphomas, particularly Burkitt lymphoma (BL). We linked the genesis of the BL-like tumors to antigen stimulus in three ways. First, in reconstruction experiments, stimulation of B cells by an autoantigen in the presence of overexpressed MYC gave rise to BL-like tumors that were, in turn, dependent on both MYC and the antigen for survival and proliferation. Second, genetic disruption of the pathway that mediates signaling from the BCR promptly killed cells of the BL-like tumors as well as the tumors resembling B-CLL. And third, growth of the murine BL could be inhibited by any of three distinctive immunosuppressants, in accord with the dependence of the tumors on antigen-induced signaling. Together, our results provide direct evidence that antigenic stimulation can participate in lymphomagenesis, point to a potential role for the constitutive BCR as well, and sustain the view that the constitutive BCR gives rise to signals different from those elicited by antigen. The mouse models described here should be useful in exploring further the pathogenesis of lymphomas, and in preclinical testing of new therapeutics. It has long been suspected that the malignant proliferation of B lymphocytes known as lymphomas might represent a perversion of how the cells normally respond to antigen. In particular, the molecular receptor on the surface of the cells that signals the presence of antigen might be abnormally active in lymphomas. We have tested this hypothesis by engineering the genome of mice so that virtually all of the B cells are commandeered by a single version of the surface receptor, then stimulated that receptor with the molecule it is designed to recognize. Our results indicate that both the unstimulated and stimulated states of the receptor can cooperate with an oncogene known as MYC in the genesis of lymphomas. But the two states of the receptor give rise to different forms of lymphoma. In particular, the stimulated form cooperates with MYC to produce a disease that closely resembles Burkitt lymphoma. These results illuminate the mechanisms that are responsible for lymphomas and could inform the development of new strategies to treat the disease. A series of genetically engineered mice were used to substantiate a long-standing speculation that chronic immune-stimulus may be involved in the genesis of certain lymphomas, illuminating the pathogenesis of B cell lymphomas and suggesting new strategies to treat several forms of this malignancy, including Burkitt lymphoma.
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影响因子：
5.4
作者：
Dull, T;Zufferey, R;Naldini, L
通讯作者：
Naldini, L
B淋巴细胞抗原受体的配体非依赖性信号传导及其在B淋巴细胞中阳性选择中的作用。
影响因子：
15.3
作者：
Bannish, G;Fuentes-Panana, E M;Cambier, J C;Pear, W S;Monroe, J G
通讯作者：
Monroe, J G
在没有替代光链成分的情况下，V（d）J-聚合酶机械的表面MU重链信号下调。
影响因子：
15.3
作者：
Galler, GR;Mundt, C;Parker, M;Pelanda, R;Mårtensson, IL;Winkler, TH
通讯作者：
Winkler, TH
DOI：
10.1111/j.1349-7006.1992.tb00099.x
发表时间：
1992-03-01
期刊：
JAPANESE JOURNAL OF CANCER RESEARCH
影响因子：
--
作者：
AKAGI, K;MIYAZAKI, J;YAMAMURA, K
通讯作者：
YAMAMURA, K
影响因子：
11.4
作者：
BERNARD, O;CORY, S;ADAMS, JM
通讯作者：
ADAMS, JM