Distinct mechanisms lead to <i>HPRT</i> gene mutations in leukemic cells

Lin, Ying‐Wei; Perkins, Jonathan J.; Zhang, Zhenhua; Aplan, Peter D.

doi:10.1002/gcc.20005

Cited by 9 publications

(6 citation statements)

References 51 publications

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“…These results are consistent with a role for recombination repair, exemplified by breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) mutations, in these breast tumor cell lines (27). Of note, these types of mutations have been found previously in several T-cell leukemic cell lines (16,28). However, we noted a modest increase in transitions and transversions consistent with decreased MMR in these cells.…”

Section: Resultssupporting

confidence: 92%

Mutator activity induced by microRNA-155 ( miR-155 ) links inflammation and cancer

Tili

Michaille

Wernicke

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

228

190

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Infection-driven inflammation has been implicated in the pathogenesis of ∼15-20% of human tumors. Expression of microRNA-155 (miR-155) is elevated during innate immune response and autoimmune disorders as well as in various malignancies. However, the molecular mechanisms providing miR-155 with its oncogenic properties remain unclear. We examined the effects of miR-155 overexpression and proinflammatory environment on the frequency of spontaneous hypoxanthine phosphoribosyltransferase (HPRT) mutations that can be detected based on the resistance to 6-thioguanine. Both miR-155 overexpression and inflammatory environment increased the frequency of HPRT mutations and down-regulated WEE1 (WEE1 homolog-S. pombe), a kinase that blocks cell-cycle progression. The increased frequency of HPRT mutation was only modestly attributable to defects in mismatch repair machinery. This result suggests that miR-155 enhances the mutation rate by simultaneously targeting different genes that suppress mutations and decreasing the efficiency of DNA safeguard mechanisms by targeting of cell-cycle regulators such as WEE1. By simultaneously targeting tumor suppressor genes and inducing a mutator phenotype, miR-155 may allow the selection of gene alterations required for tumor development and progression. Hence, we anticipate that the development of drugs reducing endogenous miR-155 levels might be key in the treatment of inflammation-related cancers.genome stability | LPS | TNF | proliferation | transgenic mice I t now is well established that chronic and persistent inflammation contributes to cancer development (1-3). Infectiondriven inflammation is involved in the pathogenesis of ∼15-20% of human tumors, and tumor-infiltrating leukocytes, such as monocytes/macrophages, T lymphocytes, and neutrophils, are prime regulators of cancer inflammation (1-3). Furthermore, even tumors that are not epidemiologically linked to pathogens are characterized by the presence of an inflammatory component in their microenvironment.MicroRNAs (miR) are a class of short, noncoding RNAs that are implicated in many aspects of cell biology. MiR-155 is implicated in hematopoiesis, the innate and acquired immune response, and autoimmune disorders (4-9). A direct link between elevated levels of miR-155 and the formation and development of tumors such as leukemias and breast, lung, or gastric cancers has been established recently (4,5,(9)(10)(11)(12). Thus, transgenic mice overexpressing miR-155 in B cells or hematopoietic stem cells show enhanced proliferative disorder that results in high-grade lymphoma (13,14). Being oncogenic and implicated in inflammation, miR-155 is the prototype of microRNAs that stand between inflammation and carcinogenesis. However, the molecular mechanisms behind this link remain unclear. Because miR-155 targets transcripts implicated in DNA repair (15), we evaluated the mutator activity of miR-155 and that of the miR-155-linked inflammatory environment as a potential mechanism connecting inflammation and cancer. In this study we report t...

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Section: Resultssupporting

confidence: 92%

Mutator activity induced by microRNA-155 ( miR-155 ) links inflammation and cancer

Tili

Michaille

Wernicke

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

228

190

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“…In some studies, there is no difference in the mutant frequency between normal and tumor cells in culture [Elmore et al, 1983]. In other studies, the difference is marked [Lin et al, 2004]. It is likely that enhanced mutagenesis could be disadvantageous during the later stages of tumor progression and thus cells that harbor too many mutations may be eliminated from the population.…”

Section: Is a Mutator Phenotype An Early Event In Tumor Progression?mentioning

confidence: 96%

Mutator phenotype in cancer: Timing and perspectives

Bielas

Loeb

2005

Environ and Mol Mutagen

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Normal human cells replicate their DNA with exceptional accuracy. During every division cycle, each daughter cell receives a full and accurate complement of genetic information. It has been estimated that approximately one error occurs during DNA replication for each 10(9) to 10(10) nucleotides polymerized. Stem cells, the cells that are progenitors of cancer, may replicate their genes even more accurately. In contrast, the malignant cells that constitute a tumor are markedly heterogeneous and exhibit multiple chromosomal abnormalities and alterations in the nucleotide sequence of DNA. To account for the disparity between the rarity of mutations in normal cells and the large numbers of mutations present in cancer, we initially hypothesized that during tumor progression, cancer cells must exhibit a mutator phenotype. In this perspective, we summarize the evidence supporting a mutator phenotype in human cancer, analyze recent measurements of mutations in human cancer, consider the timing for the expression of a mutator phenotype, and focus on the important consequences of large numbers of random mutations in human tumors.

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“…Others have calculated μ by the formula Δ f = μ × Δ d , after depletion of pre-existing HPRT mutants using hypoxanthine-aminopterin-thymidine (HAT) [10]. Whereas colon cancers have exhibited an elevated μ [11], mutant frequency data has been variable for hematologic malignancies [12], which some have attributed to metabolic cooperation [13,14]. …”

Section: 0 Introductionmentioning

confidence: 99%

A quantitative analysis of genomic instability in lymphoid and plasma cell neoplasms based on the PIG-A gene

Araten

Martínez-Climent

Perle

et al. 2010

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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It has been proposed that hypermutability is necessary to account for the high frequency of mutations in cancer. However, historically, the mutation rate (μ) has been difficult to measure directly, and increased cell turnover or selection could provide an alternative explanation. We recently developed an assay for μ using PIG-A as a sentinel gene and estimated that its average value is 10.6 × 10 -7 mutations per cell division in B-lymphoblastoid cell lines (BLCLs) from normal donors. Here we have measured μ in human malignancies and found that it was elevated in cell lines derived from T cell acute lymphoblastic leukemia, mantle cell lymphoma, follicular lymphoma in transformed phase, and 2 plasma cell neoplasms. In contrast, μ was much lower in a marginal zone lymphoma cell line and 5 other plasma cell neoplasms. The highest μ value that we measured, 3286 × 10 -7 , is 2 orders of magnitude above the range we have observed in non-malignant human cells. We conclude that the type of genomic instability detected in this assay is a common but not universal feature of hematologic malignancies. IntroductionA model sentinel gene to measure spontaneous somatic mutations must be non-essential for growth or viability, and the mutant phenotype must be detectable among a vastly larger population of normal cells. Since a single mutation conferring loss of function could be complemented by the wild type allele on the homologous chromosome, most autosomal genes are not suitable for this purpose. However, due to hemizygosity in males and X-inactivation in females, a single mutation is sufficient to inactivate X-linked genes. For example, among lymphocytes in normal adults, resistance to 6-thioguanine occurs as a consequence of a spontaneous inactivating mutation in HPRT (Xq26-q27.2), at a frequency (f) of ∼ 2 -10 × 10 -6 [1].Corresponding author. David J. Araten, MD, NYU Cancer Center, 7 th Floor, 160 East 34 th Street, New York, NY 10016. 212-731-5186 (office); 212-731-5540 (fax). David.Araten@nyumc.org. There are no conflicts of interest to report.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. While f represents the proportion of mutants within a population, the mutation rate (μ) represents the probability of a new mutation per cell division. If mutations are growth-neutral, f will increase over time according to the formula Δf = μ × Δd, where d represents number of cell divisions. By analysis of f values for HPRT in human population groups of different ages and estimates for Δd in human lymphocytes in vivo, it has been proposed that the normal μ value for this gene is ∼8.4 ×...

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Distinct mechanisms lead to HPRT gene mutations in leukemic cells

Cited by 9 publications

References 51 publications

Mutator activity induced by microRNA-155 ( miR-155 ) links inflammation and cancer

Mutator activity induced by microRNA-155 ( miR-155 ) links inflammation and cancer

Mutator phenotype in cancer: Timing and perspectives

A quantitative analysis of genomic instability in lymphoid and plasma cell neoplasms based on the PIG-A gene

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