Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells
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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.
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Impaired DNA mismatch repair plays a role in leukemogenesis.
“several lines of evidence support a role of impaired DNA mismatch repair (MMR) in leukemogenesis23–25.”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [25]
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Self-citation
- Authors
- Diouf, B., Cheng, Q., Krynetskaia, N. F., Yang, W., Cheok, M., Pei, D., Fan, Y., Cheng, C., Krynetskiy, E. Y., Geng, H., Chen, S., Thierfelder, W. E., Mullighan, C. G., Downing, J. R., Hsieh, P., Pui, C.-H., Relling, M. V., & Evans, W. E.
- Affiliations
- St. Jude Children's Research Hospital (US)
- National Institutes of Health (US)
- Corresponding author
- Evans, William E
- ORCID
- Venue
- Nature Medicine
- Published
- 2011-09-25
- Volume
- 17
- Issue
- 10
- Pages
- 1298-1303
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3192247
- OpenAlex
- W2070569107
- Cited by
- 129
- References
- 36
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 3 · 2022: 15 · 2021: 12 · 2020: 18 · 2019: 9 · 2018: 5 · 2017: 10 · 2016: 8 · 2015: 5 · 2014: 11 · 2013: 14 · 2012: 7
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R37-CA36401, CA21765, R37CA036401, P30CA021765)
- National Institute of General Medical Sciences (U01GM92666, U01GM092666)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- mismatch repair deficiency, somatic deletions, acute lymphoblastic leukemia, pediatric leukemia, drug resistance, thiopurine resistance, mTOR, HERC1, protein kinase C zeta, PIK3C2B, colorectal cancer, protein degradation
- MeSH terms
- Protein Kinase C zeta, Adult, Child, Humans, Protein Kinase C, Thioguanine, Blotting, Western, Proportional Hazards Models, Gene Deletion, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Polymorphism, Single Nucleotide, Guanine Nucleotide Exchange Factors, Ubiquitin-Protein Ligases, Cell Line, Tumor, MutS Homolog 2 Protein, DNA Mismatch Repair, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Gene Knockdown Techniques, Class II Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases
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