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.

Public Health Relevance

Somatic mutations and deletions on chromosome 17p are common in complex karyotype AML, where they are associated with a dismal prognosis. This project builds on preliminary evidence that chromosome 17p lesions contribute more to leukemia than simply inactivating p53, and will combine genomics, functional genetics, and mouse models to explore the molecular basis for how distinct 17p lesions effect leukemogenesis and therapy response. Results will provide insight into how 17p lesions contribute to leukemia and contribute new insights into the most frequent chromosomal lesion occurring across all cancer types.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Mufson, R Allan
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Sloan-Kettering Institute for Cancer Research
New York
United States
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