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DNA Mismatch Repair Status Affects Cellular Response to Ara-C and Other Anti-Leukemic Nucleoside Analogs

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DNA Mismatch Repair Status Affects Cellular Response to Ara-C and Other Anti-Leukemic Nucleoside Analogs Letters to the Editor 1046 grants CA30969, CA29139, CA98543, CA98413, and CA114766 for unfavorable early treatment response. Blood 2009; 114: awarded to the Children’s Oncology Group. 1053–1062. 4 Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, LYu1, ML Slovak2,5, K Mannoor1, C Chen1, SP Hunger3, Ahn Y et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 2009; 114: AJ Carroll4, RA Schultz2, LG Shaffer2, BC Ballif2 and Y Ning1 1 647–650. Department of Pathology, University of Maryland School 5 Duker AL, Ballif BC, Bawle EV, Person RE, Mahadevan S, of Medicine, Baltimore, MD, USA; 2 Alliman S et al. Paternally inherited microdeletion at 15q11.2 Division of Cytogenetics, Signature Genomic Laboratories, confirms a significant role for the SNORD116 C/D box snoRNA Spokane, WA, USA; 3 cluster in Prader-Willi syndrome. Eur J Hum Genet 2010; 18: Center for Cancer and Blood Disorders, University of 1196–1201. Colorado Denver School of Medicine, Aurora, CO, USA and 6 Raschke S, Balz V, Efferth T, Schulz WA, Florl AR. Homozygous 4 Department of Genetics, University of Alabama at deletions of CDKN2A caused by alternative mechanisms in various Birmingham, Birmingham, AL, USA human cancer cell lines. Genes Chromosomes Cancer 2005; 42: E-mail: [email protected] 58–67. 5Current address: Division of Cytogenetics, Quest Diagnostics 7 De Keersmaecker K, Marynen P, Cools J. Genetic insights in the Nichols Institute, Chantilly, VA, USA. pathogenesis of T-cell acute lymphoblastic leukemia. Haemato- logica 2005; 90: 1116–1127. 8 Colaizzo-Anas T, Aplan PD. Cloning and characterization of the SIL promoter. Biochim Biophys Acta 2003; 1625: 207–213. References 9 Van Vlierberghe P, van Grotel M, Tchinda J, Lee C, Beverloo HB, van der Spek PJ et al. The recurrent SET-NUP214 fusion as a new 1 Schultz KR, Pullen DJ, Sather HN, Shuster JJ, Devidas M, Borowitz HOXA activation mechanism in pediatric T-cell acute lympho- MJ et al. Risk- and response-based classification of childhood blastic leukemia. Blood 2008; 111: 4668–4680. B-precursor acute lymphoblastic leukemia: a combined analysis of 10 Kleppe M, Lahortiga I, El Chaar T, De Keersmaecker K, Mentens N, prognostic markers from the Pediatric Oncology Group (POG) and Graux C et al. Deletion of the protein tyrosine phosphatase gene Children’s Cancer Group (CCG). Blood 2007; 109: 926–935. PTPN2 in T-cell acute lymphoblastic leukemia. Nat Genet 2010; 2 Van Vlierberghe P, Homminga I, Zuurbier L, Gladdines-Buijs J, van 42: 530–535. Wering ER, Horstmann M et al. Cooperative genetic defects in 11 Mendell JT. miRiad roles for the miR-17-92 cluster in development TLX3 rearranged pediatric T-ALL. Leukemia 2008; 22: 762–770. and disease. Cell 2008; 133: 217–222. 3 Remke M, Pfister S, Kox C, Toedt G, Becker N, Benner A et al. 12 Mavrakis KJ, Wolfe AL, Oricchio E, Palomero T, de Keersmaecker High-resolution genomic profiling of childhood T-ALL reveals K, McJunkin K et al. Genome-wide RNA-mediated interference frequent copy-number alterations affecting the TGF-beta and PI3K- screen identifies miR-19 targets in Notch-induced T-cell acute AKT pathways and deletions at 6q15-16.1 as a genomic marker lymphoblastic leukaemia. Nat Cell Biol 2010; 12: 372–379. DNA mismatch repair status affects cellular response to Ara-C and other anti-leukemic nucleoside analogs Leukemia (2011) 25, 1046–1049; doi:10.1038/leu.2011.38; mechanisms leading to cell death remain unclear, although one published online 4 March 2011 hypothesis suggests that recognition of O6-MeG:T or Me6-TG:T mispairs in DNA by MutSa leads to repeated abortive repair, Nucleoside analogs form the backbone of therapeutic regimes ultimately resulting in the formation of pro-cytotoxic DNA for acute myeloid leukemia (AML) and are used to treat strand breaks.1 MMR-defective cells lack the capacity to numerous other hematological malignancies, including B-cell recognize mispairs and consequently demonstrate a ‘tolerant’ acute lymphoblastic leukemia and Hodgkin lymphoma. Chemo- phenotype and chemoresistance. resistance presents a major obstacle to the successful treatment The cytotoxicity of Ara-C is mediated in part by incorporation of both relapsed and therapy-related AML (t-AML), and altered into replicating DNA leading to inhibition of chain extension, DNA repair function is one possible mechanism underlying this stalling of replication forks, activation of the S-phase checkpoint phenotype. and cell cycle arrest. However, the presence of Ara-C residues at Microsatellite instability, indicative of defective DNA internucleotide linkage positions in leukemic cells treated mismatch repair (MMR) is a rare finding in de novo AML but in vitro provides evidence that Ara-C is not an absolute chain is common in relapsed AML and t-AML, in which it is reported terminator and that extension can occur following incorporation to occur in 30–90% of cases.1–3 DNA MMR is responsible for into DNA.4 Given this, we hypothesized that incorporation of maintaining the integrity of the genome by mediating repair of Ara-C might generate a substrate recognized by the MMR spontaneous DNA damage arising during DNA replication. The machinery and that, as in the case of 6-TG, cellular response to MutSa heterodimer (comprising hMSH2 and hMSH6) initiates Ara-C-induced toxicity is influenced by MMR status. repair of base/base mispairs. A second complex, MutSb MT-1, a B-lymphoblastoid cell line mutated in both copies of (comprising hMSH2 and hMSH3), mediates repair of short- MSH6, expressed almost negligible levels of hMSH6 protein and long insertion-deletion loops, but has no activity toward compared with its MMR-proficient parental cell line, TK6 mispairs. Subsequent recruitment of the MutLa heterodimer (assessed by western immunoblotting). Loss of MSH6 was (hMLH1 and hPMS2) facilitates strand excision and gap filling, accompanied by an approximate 50% decrease in hMSH2 restoring the DNA to its original structure. Paradoxically, protein but no difference in hMSH3 (Figure 1a). MT-1 was less functional DNA MMR facilitates cytotoxicity of certain sensitive to the cytotoxic effects of the methylating agent chemotherapeutic agents, including methylating agents and N-methyl-N-nitrosourea (MNU) (Figure 1b) and to 6-TG the base analog 6-thioguanine (6-TG). In both the cases, the (Figure 1c) compared with parental TK6 cells, consistent with Leukemia Letters to the Editor 1047 the established tolerance of MT-1 to these agents and its known defect in DNA MMR. MT-1 and TK6 also displayed differential toxicity to Ara-C, consistent with a role for DNA MMR in affecting cellular response to this nucleoside analog. However, in contrast to the phenotype observed following treatment with 6-TG, DNA MMR-defective MT-1 cells were acutely sensitive to Ara-C relative to parental TK6 cells (Figure 1d). We next investigated whether MMR status affects cellular response to other nucleoside analogs used in the treatment of hematological malignancy. Clofarabine and fludarabine, like Ara-C, are good substrates for incorporation into DNA by DNA polymerases. Cellular response following treatment with each of these agents was consistent with that observed following treatment with Ara-C, in that MMR-defective MT-1 cells were more sensitive relative to MMR-competent parental TK6 cells (Figures 1e and f). There was no significant difference in sensitivity to UV radiation between TK6 and MT-1 (Figure 1g). Given that UV radiation is not thought to induce lesions, which are substrates for DNA MMR, this finding excludes a generic DNA repair defect in MT-1. These data suggest that the role of DNA MMR as a modulator of cellular response to nucleoside analogs are not limited to the pyrimidine analog Ara-C, but can be extended to other arabinosyl nucleoside analogs. Moreover, the mode of interaction is clearly different to that reported for 6-TG and methylating agents. To investigate the effect of defects in specific components of DNA MMR, we developed fully isogenic cell line pairs using short-hairpin RNA-mediated gene interference to reduce expression of MSH2, MSH3 or MSH6 in lymphoid cells (TK6) and myeloid leukemic cells (HL-60) (Figure 2a). Lentiviral particles containing short-hairpin RNA constructs targeting MSH2, MSH3 or MSH6 were used to transduce TK6 or HL-60, according to the manufacturers protocols (Sigma-Aldrich, Dorset, UK). Stably transfected cells were selected and maintained by transfer to cell culture medium supplemented with 2 mg/ml puromycin. Knockdown of MSH2 resulted in complete loss of hMSH2 protein in both HL-60 (HL-60 MSH2i) and TK6 (TK6 MSH2i), accompanied by complete loss of both hMSH3 and hMSH6. MSH3 knockdown resulted in near- complete loss (approximately 95%) of hMSH3 in both HL-60 (HL-60 MSH3i) and TK6 (TK6 MSH3i), but there was no observed effect on hMSH2 or hMSH6. Knockdown of MSH6 completely abolished hMSH6 protein (HL-60 MSH6i and TK6 MSH6i), and was accompanied by an approximate 50% decrease in hMSH2 but did not affect hMSH3 expression relative to respective parental cell lines. Cells depleted for either hMSH2 or hMSH6 demonstrated tolerance to the cytotoxic effects of MNU (Figure 2b) and 6-TG (Figure 2c) compared with respective parental cell lines, consistent with the phenotype expected in MutSa-defective cells when exposed to these agents. Depletion of hMSH3 had no effect on cytotoxicity induced by MNU or 6-TG (Figures 2b and c), confirming that the MutSb complex has no role in mediating cytotoxicity in response to these agents. Figure 1 MSH6 mutation modulates nucleoside analog-induced Like MSH6-mutated MT-1, cells depleted in hMSH2 or cytotoxicity in MMR-defective lymphoblastoid cells. (a)Western hMSH6 were sensitive to the cytotoxic effects of Ara-C, immunoblotting of MutS components (MSH2, MSH3 and MSH6) in MMR- clofarabine and fludarabine relative to their respective parental proficient TK6 and its MMR-deficient subclone MT-1.
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