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Msh2 Deficiency Attenuates But Does Not Abolish Thiopurine Hematopoietic Toxicity in Msh2^-/- Mice

Departments of Pharmaceutical Sciences (N.F.K., T.L.B., E.Y.K., W.D., J.C.P., W.E.E.) and Hematology-Oncology (C.-H.P.), St. Jude Children's Research Hospital, Memphis, Tennessee; and University of Tennessee, Memphis, Tennessee (N.F.K., E.Y.K., C.-H.P., W.E.E.)

The amount of MSH2 protein, a major component of the mismatch repair system, was found to differ >10-fold in leukemia cells from children with newly diagnosed acute lymphoblastic leukemia, with a subgroup of patients (17%) having undetectable MSH2 protein. We therefore used a murine Msh2 knockout model to elucidate the in vivo importance of MSH2 protein expression in determining thiopurine hematopoietic cytotoxicity. After mercaptopurine (MP) treatment (30 mg/kg/day for 14 days), there was a significantly greater decrease in circulating leukocytes in Msh2^+/+ and Msh2^+/- mice when compared with Msh2^-/- mice (p < 0.002). Likewise, the decrease in erythrocyte counts was more prominent in mice with at least one functional Msh2 allele. MP doses of more than 50 mg/kg/day for 14 days resulted in treatment-related deaths, but Msh2^-/- mice had a significant survival advantage (p = 0.02). Murine embryonic fibroblasts (MEFs) from Msh2^+/+ mice also exhibited increased sensitivity to MP when compared with MEFs from Msh2^-/- mice (IC₅₀, 3.8 ± 0.1 µM versus 11.9 ± 1.3 µM, p < 0.001). After MP treatment, deoxythioguanosine incorporation into DNA was similar in mice and MEFs with each of the Msh2 genotypes. Electromobility shift assay experiments identified an Msh2-containing GT- or G^ST-DNA-nuclear protein complex in Msh2^+/+ but not Msh2^-/- MEFs. Together, these findings establish that hematopoietic toxicity in vivo after treatment with mercaptopurine is attenuated but not abolished by MSH2 deficiency.

Address correspondence to: Dr. William E. Evans, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. E-mail: william.evans{at}stjude.org

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