Molecular Mechanisms of Lymphomagenesis

描述（由申请人提供）：本研究的目的是确定小鼠B淋巴样癌模型中复发性细胞遗传学病变的功能作用，并阐明特征性核型不稳定性形成的机制。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及其后果，人们知之甚少。影响染色体4q21或11q23的细胞遗传学异常在淋巴样恶性肿瘤中很常见，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，与许多可能的伙伴产生MLL基因的致癌融合，是常见的；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重排通常预示预后不良，尤其是在婴儿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的缺失也与Richter综合征有关，其特征是慢性淋巴细胞白血病向高级别非霍奇金淋巴瘤（NHL）的转变。里希特氏综合征导致肿瘤加速生长，临床恶化，并对常规治疗产生耐药性。新出现的证据表明，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断裂修复因子的突变与许多人类肿瘤有关，包括Richter综合征。缺乏DNA断裂修复非同源末端连接通路六种已知组分中的任何一种和肿瘤抑制因子p53（由Trp53编码，统称为NHEJ/Trp53小鼠）的小鼠，会发展为具有极高外显率的侵袭性多灶祖细胞(pro)-B细胞淋巴瘤。引人注目的是，在Lig4/Trp53肿瘤的5号染色体（CNA5）和9号染色体（CNA9）上观察到的拷贝数异常（CNA）分别影响与人类4q21和11q23相关的区域。因此，NHEJ/Trp53小鼠为在这些染色体位置具有na型病变的淋巴样癌提供了动物模型，并将对人类淋巴样癌（如儿童B-ALL和Richter’s综合征）目前未知的方面提供见解。因此，这些研究将为改进诊断方法的发展，以及新的、可能个体化的治疗方法的制定和临床发展奠定基础。

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.