Immune Correlates and Mechanisms of Perinatal Cytomegalovirus Infection and Later Life ALL Development

摘要 急性淋巴细胞性白血病(ALL)是儿童最常见的恶性肿瘤，疑似起源于产前。 在大多数情况下。尽管近90%的患者能活到成年，但治疗具有破坏性 长期的健康影响和初级预防仍然是肿瘤学研究的典型目标。儿童 ALL患者在出生时表现出炎性细胞因子水平的变化，并经历更多的内科疾病 诊断出早期感染，表明早期感染可能是一种可改变的病原体。我们 最近证实，ALL患儿的前处理骨髓标本普遍存在 巨细胞病毒(CMV)感染。268名继续留学儿童新生儿血液样本的筛查 发展为ALL的270名非癌症对照儿童显示，所有患者的发病率几乎是对照组的4倍 出生时可能在血液中检测到巨细胞病毒(OR=3.71，P=0.0016)，提示先天性巨细胞病毒 感染是一个完全危险的因素。巨细胞病毒是世界上最常见的先天性感染，每150名婴儿中就有1人感染。 出生前感染CMV可能对包括T细胞在内的发育中的免疫系统产生重大影响 激活和中枢耐受。CMV拥有所有人类病毒病原体中最大的基因组，并携带许多 免疫逃避基因，表明CMV调节宿主免疫系统以逃避免疫监视。 这种巨细胞病毒诱导的免疫调节机制还知之甚少；然而，其他 致癌病毒可以诱导宿主表观基因组发生广泛的甲基化变化。病毒诱导 表观遗传变化可能会改变发育中的免疫系统的转录格局，并对 影响造血过程中的血统承诺和宿主免疫监控，从而增强所有 风险。因此，确定先天性巨细胞病毒感染和白血病相关的调节失调之间的相互作用 早期生命中的基因是建立先天性巨细胞病毒感染之间机制联系的重要一步 以及所有风险，这是一个潜在的疫苗可预防的癌症风险因素。我们假设先天性巨细胞病毒感染 在发育中的胎儿中诱导表观遗传学和免疫学变化，从而增加发展ALL的风险 在童年时期。使用匹配的CMV感染、暴露和未暴露的病例对照样本 来自卡罗莱纳州脐血库的脐带血捐献者，我们将鉴定表观遗传学和免疫学 先天性巨细胞病毒感染的后果。然后我们将确定CMV感染相关的表观遗传学和 免疫学变化在后来发展为ALL的儿童的新生儿血点中重现。 最后，我们将确定是否所有已知的易感变异通过以下方式改变先天性CMV感染的风险 比较感染了CMV的脐带血捐献者和未感染的对照组中这些变异的频率。这些 研究将阐明先天性巨细胞病毒感染对晚期癌症风险的作用，并有助于确定可改变的 可以减轻与最常见的儿童癌症相关的公共卫生负担的早期生活因素。

ABSTRACT Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, has a suspected prenatal origin in a majority of cases. Although nearly 90% of ALL patients survive into adulthood, treatment has devastating long-term health effects and primary prevention remains the quintessential goal of oncology research. Children who develop ALL exhibit alterations in inflammatory cytokine levels at birth and experience more medically diagnosed early-life infections, suggesting that early-life infections may be a modifiable etiologic agent. We recently demonstrated that pretreatment bone marrow specimens from children with ALL had prevalent cytomegalovirus (CMV) infection. Screening of archived newborn blood samples from 268 children who went on to develop ALL and 270 cancer-free control children demonstrated that ALL patients were nearly 4-times more likely to have detectable CMV in their blood at birth (OR=3.71, P=0.0016), suggesting that congenital CMV infection is an ALL risk factor. CMV is the most common congenital infection worldwide, affecting 1 in 150 infants. CMV infection prior to birth likely has a significant impact on the developing immune system, including T cell activation and central tolerance. CMV has the largest genome of any human viral pathogen and harbors many immune-evasion genes, indicating that CMV modulates the host immune system to escape immunosurveillance. The mechanisms underlying this CMV-induced immune modulation are poorly understood; however, other oncogenic viruses can induce widespread methylation changes to the host epigenome. Virally-induced epigenetic changes may alter the transcriptional landscape of the developing immune system and negatively impact both lineage commitment during hematopoiesis and host immunosurveillance, thereby augmenting ALL risk. Thus, defining the interaction between congenital CMV infection and dysregulation of leukemia-associated genes in early life is an important step toward establishing the mechanistic link between congenital CMV infection and ALL risk, a potentially vaccine-preventable cancer risk factor. We hypothesize that congenital CMV infection induces epigenetic and immunologic changes in the developing fetus that contribute to risk of developing ALL during childhood. Using a matched case-control sample of CMV-infected, CMV-exposed, and CMV-unexposed cord blood donors from the Carolinas Cord Blood Bank, we will identify the epigenetic and immunologic consequences of congenital CMV infection. We will then determine if CMV infection-associated epigenetic and immunologic changes are recapitulated in newborn blood spots from children who went on to develop ALL. Finally, we will determine whether known ALL susceptibility variants modify risk of congenital CMV infection by comparing the frequency of these variants in CMV-infected cord blood donors to uninfected controls. These studies will elucidate the role of congenital CMV infection on later cancer risk and help to identify modifiable early-life factors that can reduce the public health burden associated with the most common cancer of childhood.