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

 描述（由申请人提供）：TP 53突变在治疗相关性髓样瘤（tMN）和复杂核型急性髓性白血病（CK-AML）中很常见，它们与化疗耐药性相关，是任何白血病基因型中最严重的疾病之一。这些突变通常出现在染色体构型中，涉及一个TP 53等位基因中的错义突变和通过涉及17号染色体[del（17 p）]的部分或全部短臂的大染色体缺失而丢失其余野生型TP 53等位基因。虽然这些事件清楚地表明了p53的肿瘤抑制功能，但新出现的数据表明，17 p上的体细胞改变具有额外的癌症表型。例如，突变型p53蛋白具有促进更具侵袭性的癌症行为的功能获得活性，并且与杂合性缺失相关的大的17 p缺失可以减弱一个或多个连锁的单倍不足肿瘤抑制基因。由于tMN和CK-AML中17 p丢失经常与5 q和7 q丢失一起发生，这些数据意味着这种白血病是通过非连锁和连锁的两次打击和单倍不足肿瘤抑制基因之间的复杂相互作用而产生的。为了了解17 p病变对AML生物学的影响，我们将开发具有染色体17 p构型的小鼠模型，这些构型更准确地反映了人类疾病，并研究这些构型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，解释所观察到的生物效应。最后，我们将与其他MKSCC研究人员合作，确认我们在小鼠中的发现与人类疾病的相关性。我们的项目是基于大量以前的工作和初步结果，并利用我们小组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方法来研究TP 53突变和大染色体缺失。我们希望，拟议工作的成功完成将确定AML中的17 p病变是否以及如何影响白血病表型，而不仅仅是使TP 53失活，并在这样做的过程中，为人类癌症中最常见的体细胞事件提供新的见解。更广泛地说，该项目将为研究其他癌症相关的体细胞缺失提供蓝图，这些缺失在所有人类癌症中非常常见，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.