Molecular Mechanisms of Lymphomagenesis

描述（由申请方提供）：本研究的目的是确定小鼠B淋巴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。虽然基因组不稳定性是公认的标志，但对许多肿瘤，包括淋巴瘤和白血病，基因组不稳定性背后的分子机制及其后果知之甚少。影响染色体4 q21或11 q23的细胞遗传学异常常见于淋巴恶性肿瘤，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11 q23的易位，产生MLL基因与许多可能的伴侣的致癌融合，是常见的;其他异常，如4 q21扩增和/或11 q23缺失，虽然不太常见，也会发生。11 q23重排通常预示预后不良，尤其是在婴儿B-ALL患者中，11 q23缺失的恶性肿瘤往往比相同区域平衡易位的恶性肿瘤表现出更大的核型不稳定性。11 q23的缺失也与Richter综合征有关，其特征是慢性淋巴细胞白血病转化为高级别非霍奇金淋巴瘤（NHL）。里希特综合征导致肿瘤加速生长、临床恶化和对常规治疗的抵抗。新出现的证据表明，DNA双链断裂修复的缺陷可导致致癌基因组的不稳定性，为了支持这一观点，DNA断裂修复因子的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种已知组分中的任何一种和肿瘤抑制因子p53（由Trp 53编码;统称为NHEJ/Trp 53小鼠）的小鼠发展为具有极高转移率的侵袭性多灶性祖（原）-B细胞淋巴瘤。引人注目的是，在Lig 4/Trp 53肿瘤中的5号染色体（CNA 5）和9号染色体（CNA 9）上观察到的拷贝数异常（CNA）分别影响与人类4 q21和11 q23相关的区域。因此，NHEJ/Trp 53小鼠提供了在这些染色体位置具有CNA型病变的淋巴癌的动物模型，并且将产生对人类淋巴癌的目前未知方面的见解，例如儿童B-ALL和Richter综合征。因此，这些研究将为改进诊断方法的开发以及新的、可能个性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.