Clonal heterogeneity and therapy resistance in Burkitt lymphoma

伯基特淋巴瘤是一种罕见的侵袭性淋巴腺癌，在英国每年约有200人受到影响。目前的治疗可以非常成功，但这包括强化化疗和抗体治疗。对一些人来说，这种治疗方法虽然治愈的机会最大，但毒性太大，不能使用。这些病人的结果就不太好了。对于那些能够忍受更强化治疗的儿童和成人来说，严重感染的风险很高，患者往往不得不在医院里呆很长时间，接受强效抗生素、止痛药和喂养支持。不幸的是，对于淋巴瘤复发的患者，几乎没有额外的治疗方法，治愈的机会非常有限。目前，人们对伯基特淋巴瘤复发的原因知之甚少。我们并不完全了解使患者淋巴瘤更有可能复发的基因变化，我们也不了解为什么复发的伯基特淋巴瘤对二线治疗没有反应。重要的是，我们没有关于化疗初始治疗如何导致或选择化疗耐药细胞的信息，这些细胞随后能够生长并导致复发。这项研究将发展我们对患者淋巴瘤在诊断时存在的自然变异性的理解，然后跟踪这种变化，或发展，对化疗的反应。这两个因素被认为对患者复发的几率和确定复发的性质（例如是否对不同的化疗有反应）都很重要。由于伯基特淋巴瘤是一种罕见的癌症，总体而言，患者有很好的治愈机会，因此用于开展这项工作的复发伯基特淋巴瘤样本数量有限。为了解决这个问题，我们一直在收集伯基特淋巴瘤患者的样本，我们可以用免疫系统被改变的老鼠来研究这些样本，使它们能够接受并生长人类淋巴瘤。这些免疫缺陷小鼠是目前唯一能让淋巴瘤细胞存活足够长的时间来研究它们对模拟化疗的反应的方法。移植了患者淋巴瘤细胞的小鼠将接受与人类相似但强度较低的化疗。由于没有使用最密集的治疗方法，这些小鼠最终将发展为化疗耐药淋巴瘤，然后我们能够研究这种复发疾病模型与从同一患者身上采集的初始样本之间的差异。研究人员将通过观察遗传变异（即肿瘤异质性）如何影响产生治疗耐药性的机会，以及化疗后这种异质性如何随时间变化，来研究患者样本。化学疗法对细胞行为的影响，特别是对细胞生物机制中被称为转录组的部分被开启或关闭的影响。最初，这将通过观察个体患者和小鼠的整个肿瘤来完成，但最近的技术发展意味着我们也将能够一次一个细胞地观察患者的肿瘤。通过了解导致复发风险的因素，将有可能更准确地预测哪些患者需要积极治疗，哪些患者可以用较低强度的治疗来充分治疗。这种方法可能为目前不适合治疗性化疗的老年人或不太适合的患者提供潜在的治愈性治疗。对于复发的患者，了解是什么导致了他们的治疗抵抗，将允许合理设计新的治疗策略，有更大的治愈机会。

Burkitt lymphoma is a rare aggressive cancer of the lymph glands affecting approximately 200 people per year in the UK. Current treatment can be very successful, but this involves intensive chemotherapy and antibody therapies. For some people this type of treatment, carrying the greatest chance of cure, is too toxic and cannot be given. The outcome for these patients is much less good. For those people, both children and adults, able to tolerate the more intensive treatments, there is a high risk of severe infections and patients often have to spend long periods in hospital receiving strong antibiotics to fight infection, painkillers and support with feeding. Unfortunately, for patients in whom the lymphoma relapses there are few additional therapies and very limited chance of cure.Currently, very little is known about why Burkitt lymphoma relapses. We do not fully understand the genetic changes which make a patient's lymphoma more likely to come back and we do not understand why it is that relapsed Burkitt lymphoma tends to be unresponsive to second-line therapies. Importantly, we have no information about how initial treatment with chemotherapy causes, or selects out, chemotherapy resistant cells which are then able to grow and cause a relapse. This fellowship will develop our understanding of the natural variability which exists in a patient's lymphoma at the point when they are diagnosed and then track how this changes, or evolves, in response to chemotherapy treatment. These two factors are believed to be important both for a patient's chance of suffering a relapse and in determining the nature of the relapse, for example whether it might respond to different chemotherapies. As Burkitt lymphoma is a rare cancer and, overall, patients have a good chance of cure, there are limited numbers of relapsed Burkitt lymphoma samples with which to carry out such work. In order to address this problem, we have been developing a collection of patients' samples, taken at diagnosis of Burkitt lymphoma, which we are able to study using mice with an immune system which has been altered to allow them to accept and grow the human lymphoma. These immune deficient mice are currently the only way to keep the lymphoma cells alive long enough to study how they respond to simulated chemotherapy treatment. Mice which have been transplanted with a patient's lymphoma cells will be treated with similar but less intensive chemotherapy to that used in humans. As the most intensive therapies are not used, these mice will eventually develop chemotherapy resistant lymphoma, and we are then able to study the differences between this model of relapsed disease and the initial sample taken from the same patient. Patients' samples will be studied by looking at how the genetic variability, known as tumour heterogeneity, affects the chance of developing therapy resistance and how that heterogeneity changes over time when chemotherapy is given. The effect of chemotherapy on the behaviour of the cells and especially on which parts of a cell's biological machinery, known as its transcriptome, are turned on or off. Initially this will be done by looking at whole tumours from individual patients and mice, but more recent technological developments mean that we will also be able to look at a patient's tumour one cell at a time. By understanding the factors which drive the risk of relapse it will be possible to more accurately predict those patients in need of aggressive therapy and those that may be adequately treated with less intensive treatments. Such an approach may open up potentially curative treatments to older or less fit patients who would currently not be eligible for curative chemotherapy. For patients who relapse, understanding what drives their therapy resistance will allow the rational design of new treatment strategies with a greater chance of cure.