Polycomb Group genes in murine lymphomagenesisand their impact on drug response.

用现有药物治疗淋巴瘤的成功受到耐药性的限制。导致癌症的基因和改变对癌症治疗反应的基因之间的一些关键联系已经被确定：癌细胞最初用来成为癌细胞的细胞机制，往往与癌细胞后来用来对癌症治疗产生抗药性的细胞机制相同。Polycomb家族控制着其他关键基因的表达：也就是说，它们决定了哪些基因在何时何地开启。这决定了一个细胞的行为是否正常，或者它是否会变成癌细胞。当Polycomb基因本身在错误的时间或地点表达时，它们可能导致癌症。在人类淋巴瘤中，这些基因与更具侵袭性的淋巴瘤有关。这在其他癌症如乳腺癌和前列腺癌中也得到了证实。在某些情况下，这些基因与抗癌治疗后病情恶化的癌症有关。到目前为止，还没有一项研究在受控的实验室模型中观察Polycomb组基因对治疗成功的直接影响。我们使用了在宿主实验室建立的强大的淋巴瘤实验室小鼠模型，其中c-myc癌基因在发展中的B细胞中过度表达导致淋巴瘤。该模型易于操作，这为我们提供了大量的实验控制，远远超过了使用患者样本所能实现的。两个家族成员，Bmi-1和Cbx7，导致淋巴瘤的侵袭性发展，我们将询问另外两个成员，Ezh2和Rybp是否也会这样做。我们将确定这4个基因是否导致淋巴瘤的耐药，目前使用的化疗药物和新的抗癌药物。通过增加我们对淋巴瘤耐药的了解，可以更有效地利用药物，并确定新的标记物来预测哪种药物将成功治疗特定的淋巴瘤。

The success of lymphoma treatment with current drugs is limited by drug resistance. Some crucial links between genes which cause cancer and genes which alter response to cancer treatment have been identified: the cellular machinery that cancer cells use to become cancer cells in the first place, is often the same machinery that cancer cells later use to become resistant to cancer treatments. The Polycomb Group family controls expression of other critical genes: that is, they dictate which genes are switched on, where, and when. This determines whether a cell behaves normally or whether it may turn into a cancer cell. When Polycomb Group genes themselves are expressed at the wrong time or place, they can cause cancer. In human lymphoma, these genes have been associated with more aggressive lymphoma. This has also been shown for other cancers such as breast and prostate cancer. In some cases these genes are associated with cancers that do worse following anti-cancer treatment. So far, no research has been published looking the direct impact of the Polycomb Group genes on the success of treatment in a controlled laboratory model. We have used a powerful laboratory mouse model of lymphoma, established in the host laboratory, in which over-expression of the c-myc oncogene in developing B cells causes lymphoma. This model is easy to manipulate and this provides us with a great deal of experimental control, much more than can be achieved from working with patient samples. Two family members, Bmi-1 and Cbx7, cause lymphoma to develop aggressively and we will ask whether two other members, Ezh2 and Rybp do this as well. We will determine whether these 4 genes cause drug resistance in lymphoma, with currently used chemotherapy and also with novel anti-cancer drugs. By increasing our understanding of drug resistance in lymphoma, drugs may be utilised more effectively and new markers identified to predict which drug will be successful in treating a particular lymphoma.