Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells
| Autor: | Yiping Fan, William E. Evans, Meyling Cheok, Cheng Cheng, Wenjian Yang, Peggy Hsieh, Mary V. Relling, Deqing Pei, Barthelemy Diouf, Hui Geng, Charles G. Mullighan, Siying Chen, Qing Cheng, William E. Thierfelder, Natalia F. Krynetskaia, Ching-Hon Pui, James R. Downing, Evgeny Y. Krynetskiy |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Adult
congenital hereditary and neonatal diseases and abnormalities Somatic cell Ubiquitin-Protein Ligases Blotting Western Drug resistance Biology DNA Mismatch Repair Polymorphism Single Nucleotide Article General Biochemistry Genetics and Molecular Biology Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Gene Knockdown Techniques Guanine Nucleotide Exchange Factors Humans Child Thioguanine neoplasms Gene Protein Kinase C Class II Phosphatidylinositol 3-Kinases Proportional Hazards Models 030304 developmental biology Genetics MutS Homolog 2 Protein 0303 health sciences TOR Serine-Threonine Kinases nutritional and metabolic diseases General Medicine Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease digestive system diseases 3. Good health Leukemia Drug Resistance Neoplasm MSH2 030220 oncology & carcinogenesis Cancer research DNA mismatch repair Gene Deletion |
| Zdroj: | Nature medicine |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm.2430 |
| Popis: | DNA mismatch repair enzymes (for example, MSH2) maintain genomic integrity, and their deficiency predisposes to several human cancers and to drug resistance. We found that leukemia cells from a substantial proportion of children (∼11%) with newly diagnosed acute lymphoblastic leukemia have low or undetectable MSH2 protein levels, despite abundant wild-type MSH2 mRNA. Leukemia cells with low levels of MSH2 contained partial or complete somatic deletions of one to four genes that regulate MSH2 degradation (FRAP1 (also known as MTOR), HERC1, PRKCZ and PIK3C2B); we also found these deletions in individuals with adult acute lymphoblastic leukemia (16%) and sporadic colorectal cancer (13.5%). Knockdown of these genes in human leukemia cells recapitulated the MSH2 protein deficiency by enhancing MSH2 degradation, leading to substantial reduction in DNA mismatch repair and increased resistance to thiopurines. These findings reveal a previously unrecognized mechanism whereby somatic deletions of genes regulating MSH2 degradation result in undetectable levels of MSH2 protein in leukemia cells, DNA mismatch repair deficiency and drug resistance. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|