The impact of chromosome 17p lesions on leukemogeneis and therapy response

 描述(申请人提供)：TP53突变在治疗相关的髓系肿瘤(TMN)和复杂核型急性髓系白血病(CK-AML)中很常见，它们与化疗耐药有关，是所有白血病基因型中预后最差的一种。这些突变通常发生在染色体构型中，涉及一个TP53等位基因的错义突变，以及通过涉及17号染色体的部分或全部短臂的大染色体缺失而丢失剩余的野生型TP53等位基因[del(17p)]。虽然这些事件明显抑制了P53‘S的肿瘤抑制功能，但新出现的数据表明，17P上的体细胞变化具有额外的癌症表型。例如，突变的p53蛋白具有促进更具侵袭性的癌症行为的功能获得活性，与杂合性丢失相关的大量17p缺失可能会减弱一个或多个关联的单倍体不足的肿瘤抑制基因。由于在TMN和CK-AML中经常同时发生17p丢失和5q和7q丢失，这些数据表明该白血病是通过两个非连锁和连锁的两次打击和单倍体不足的抑癌基因之间的复杂相互作用而发生的。为了了解17p病变对AML生物学的影响，我们将开发具有17p染色体配置的小鼠模型，以更准确地反映人类疾病，并研究这些配置如何影响白血病的发展和治疗反应。此外，我们将执行假设驱动和无偏见的方法，以确定特定的基因和潜在的机制，以解释观察到的生物效应。最后，我们将与其他MKSCC研究人员合作，确认我们在小鼠身上的发现与人类疾病的相关性。我们的项目基于大量以前的工作和初步结果，并利用我们团队开发的创新小鼠模型和功能基因组方法，使我们能够采取系统和全面的遗传学方法来研究TP53突变和大的染色体缺失。我们预计，拟议工作的成功完成将确定AML中的17P病变是否以及如何影响白血病表型，而不仅仅是使TP53失活，从而为人类癌症中发生的最频繁的躯体事件提供新的见解。更广泛地说，该项目将为研究其他与癌症相关的体细胞缺失提供一个蓝图，这些体细胞缺失在所有人类癌症中都非常常见，但仍然知之甚少。

 DESCRIPTION (provided by applicant): TP53 mutations are common in treatment associated myeloid neoplasia (tMN) and complex karyotype acute myeloid leukemia (CK-AML), where they are associated with chemoresistance and one of the worst prognoses of any leukemia genotype. These mutations typically arise in a chromosome configuration involving a missense mutation in one TP53 allele and loss of the remaining wild-type TP53 allele through large chromosomal deletions involving part or all of the short arm of chromosome 17 [del(17p)]. While these events clearly inactivate p53's tumor suppressive functions, emerging data indicate that the somatic alterations on 17p have additional cancer phenotypes. For example, mutant p53 proteins possess gain-of-function activities that promote more aggressive cancer behavior and the large 17p deletions associated with loss-of-heterozygosity may attenuate one or more linked haploinsufficient tumor suppressor genes. Since 17p loss often occurs together with 5q and 7q loss in tMN and CK-AML, these data imply that this leukemia arises through complex interactions between both unlinked and linked two-hit and haploinsufficient tumor suppressor genes. To understand the impact of 17p lesions on AML biology, we will develop mouse models with chromosome 17p configurations that more accurately reflect the human disease and study how these influence leukemia development and therapy response. Furthermore, we will perform hypothesis driven and non-biased approaches to identify specific genes and underlying mechanisms that explain the observed biological effects. Finally, we will work with other MKSCC investigators to confirm the relevance of our findings in mice to the human disease. Our project is based on substantial previous work and preliminary results, and exploits innovative mouse models and functional genomic methods developed in our group that allow us to take a systematic and comprehensive genetic approach towards studying TP53 mutations and large chromosomal deletions. We expect that successful completion of the proposed work will determine whether and how 17p lesions in AML impact leukemia phenotypes beyond simply inactivating TP53 and, in doing so, provide novel insights into the most frequent somatic events occurring in human cancer. More broadly, the project will provide a blueprint for studying other cancer associated somatic deletions, which are extremely common across all human cancers but remain poorly understood.