Cited by 137DNA Repair MechanismsAcute Lymphoblastic Leukemia researchGenetic factors in colorectal cancer

Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells

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Diouf, Barthelemy, Cheng, Qing, Krynetskaia, Natalia F, Yang, Wenjian, Cheok, Meyling, Pei, Deqing, Fan, Yiping, Cheng, Cheng +10 more·2011·Nature Medicine

Abstract

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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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
Venue
Nature Medicine
Published
2011-09-25
Volume
17
Issue
10
Pages
1298-1303
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
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
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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