Molecular Mechanisms of Lymphomagenesis

描述(申请人提供)：这项研究的目的是确定在小鼠B淋巴癌模型中复发的细胞遗传学病变的功能作用，并阐明特征核型不稳定性的形成机制。虽然基因组不稳定是一个公认的标志，但许多肿瘤，包括淋巴瘤和白血病，基因组不稳定背后的分子机制，以及它的后果，还知之甚少。影响染色体4q21或11q23的细胞遗传学异常在淋巴系恶性肿瘤中很常见，如套细胞淋巴瘤和Preb-ALL，后者是最常见的儿科恶性肿瘤，占所有儿童癌症诊断的近25%。涉及11q23的易位是常见的，导致MLL基因与许多可能的合作伙伴的致癌融合；其他异常，如4q21的扩增和/或11q23的缺失，虽然不太常见，但也会发生。11q23的重排通常预示着不良的预后，特别是在婴儿B-ALL患者中，11q23缺失的恶性肿瘤往往比在同一区域有平衡易位的恶性肿瘤表现出更大的核型不稳定性。11q23缺失也与里希特综合征有关，其特征是慢性淋巴细胞白血病向高度恶性非霍奇金淋巴瘤(NHL)的转化。里希特综合征导致肿瘤生长加速，临床恶化，并对传统治疗产生抵抗。新的证据表明，DNA双链断裂修复缺陷可导致致癌基因组不稳定，支持这一观点的是，DNA断裂修复因子突变与许多人类肿瘤有关，包括里希特综合征。缺乏DNA断裂修复的非同源末端连接途径的六个已知成分中的任何一个和肿瘤抑制基因P53(由TrP53编码，统称为NHEJ/TrP53小鼠)的小鼠会发生侵袭性的、具有极高外显率的多灶性祖细胞(PRO)-B细胞淋巴瘤。值得注意的是，在Lig4/Trp53肿瘤中观察到的5号染色体(CNA5)和9号染色体(CNA9)上的拷贝数异常(CNA)分别影响与人类4q21和11q23相关的区域。因此，NHEJ/Trp53小鼠提供了在这些染色体位置具有CNA类型病变的淋巴癌的动物模型，并将深入了解目前未知的人类淋巴癌的方面，如儿童B-ALL和里希特综合征。因此，这些研究将为改进诊断方法的开发以及新的、可能是个体化的治疗方法的制定和临床开发奠定基础。

DESCRIPTION (provided by applicant): The objectives of this study are to determine functional roles for recurrent cytogenetic lesions in a mouse B lymphoid cancer model, and to elucidate the mechanisms for formation of characteristic karyotypic instability. While genomic instability is a recognized hallmark, many tumors, including lymphomas and leukemias, the molecular mechanisms behind genomic instability, as well as its consequences, are poorly understood. Cytogenetic abnormalities affecting chromosomes 4q21 or 11q23 are common in lymphoid malignancies, such as mantle cell lymphoma and preB-ALL, the latter being the most common pediatric malignancy, at nearly 25% of all childhood cancer diagnoses. Translocations involving 11q23, producing oncogenic fusions of the MLL gene with numerous possible partners, are common; other abnormalities, such as amplification at 4q21 and/or deletion of 11q23, though less frequent, also occur. Rearrangements at 11q23 generally predict a poor prognosis, especially in infant B-ALL patients, and malignancies with deletions at 11q23 tend to exhibit greater karyotypic instability than those with balanced translocations in the same region. Deletions at 11q23 are also associated with Richter's syndrome, characterized by the transformation of chronic lymphocytic leukemia to high-grade non-Hodgkin's Lymphoma (NHL). Richter's syndrome leads to accelerated tumor growth, clinical deterioration, and resistance to conventional therapy. Emerging evidence suggests that defects in DNA double strand break repair can lead to oncogenic genome instability and, in support of this notion, mutations in DNA break repair factors are implicated in a number of human tumors, including Richter's syndrome. Mice deficient for any of the six known components of the nonhomologous end joining pathway of DNA break repair, and for the tumor suppressor p53 (encoded by Trp53; collectively referred to as NHEJ/Trp53 mice), develop aggressive, multi-focal progenitor (pro)-B cell lymphomas with extremely high penetrance. Strikingly, copy number abnormalities (CNA) observed on chromosomes 5 (CNA5) and 9 (CNA9) in Lig4/Trp53 tumors affect regions related to human 4q21 and 11q23, respectively. Thus, NHEJ/Trp53 mice provide an animal model for lymphoid cancers with CNA-type lesions at these chromosomal locations, and will yield insights into currently unknown facets of human lymphoid cancers, such as childhood B-ALL and Richter's syndrome. These studies will therefore lay a foundation for the development of improved diagnostic methods, as well as the formulation and clinical development of new, possibly individualized, therapeutic approaches.