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Abstract 1680 Individuals with Down syndrome have a 2% cumulative risk for the development of leukemia by the time they reach 30 years of age. In addition, as many as 5–10% of infants with Down syndrome may develop a transient myeloproliferative disorder (TMD). The molecular basis for the increased risk for hematologic disorders and other congenital developmental abnormalities with DS remains unknown. Additional genetic material from the critical Down syndrome locus at 21q22 includes the Cu/Zn superoxide dismutase gene and other genes contributing to high oxidative stress and increased endogenous DNA damage observed in cells from patients with Down syndrome. We hypothesized that functional polymorphic variants in enzymes associated with detoxification of oxidants and repair of oxidant associated DNA damage would be associated with an increased risk for the development of myeloid leukemia (ML) and TMD in children with Down syndrome. We studied the role of functional polymorphisms in the oxidant metabolizing genes, Paraoxonase 1 (PON1) and NADH/NADPH oxidase p22 phox (P22_PHOX) in the potential genetic etiology of ML/TMD in children with Down syndrome. Genotyping was conducted in 192 patients with Down Syndrome ML or TMD, and 251 healthy blood donor controls. All genotype frequencies in patients and control populations were consistent with those expected from Hardy-Weinberg equilibrium. We found that the variant PON1 Gln192Arg allele, associated with reduced free radical metabolism, occurred at a higher frequency in the Down syndrome ML/TMD population compared to healthy controls (OR, 2.71; 95% CI, 1.50–4.97; p=0.0003). Consistent with our hypothesis of increased oxidant sensitivity in these patients, we also observed decreased frequency of the protective variant P22_PHOX His72Tyr allele, purportedly associated with reduced generation of reactive oxygen species, in the Down syndrome ML/TMD population compared to healthy controls (OR, 0.48; 95% CI, 0.23–0.95; p=0.025). Notably, the variant PON1 Gln192Arg allele has also been associated with increased risk for non-Hodgkin's lymphoma in adults (Kerridge et al. Br J Haematol, 2002). Conclusion: These preliminary studies suggest that functional polymorphic variants in the oxidant metabolizing enzymes PON1 and P22_PHOX may influence risk for development of ML/TMD in children with Down syndrome. Studies to confirm these observations in a separate cohort of patients are in progress. Disclosures: No relevant conflicts of interest to declare.

Children with Down syndrome can have a wide range of developmental abnormalities related to the presence of additional genetic material from a small region of chromosome 21. Additional copies of the Cu/Zn superoxide dismutase gene and related genes at this locus are believed to contribute to high oxidative stress, and increased endogenous DNA damage and deficient repair observed in cells from patients with Down syndrome. Children with Down syndrome also have a markedly increased risk for the development of serious hematological disorders, including an approximately 20-fold increased risk for the development of acute myeloid leukemia (AML). In addition, in early infancy, as many as 10% may develop a transient myeloproliferative disorder (TMD). The basis for this overall increased risk is unknown, as are the risk factors influencing which specific patients with Down syndrome develop AML/TMD. We sought to test the hypothesis that functional polymorphisms in genes involved in oxidant metabolism and DNA repair contribute to the increased risk of AML and TMD in children with Down syndrome. We studied functional polymorphisms in the oxidant metabolizing enzyme NADPH quinone oxidoreductase 1 (NQO1), and in the DNA repair proteins X-ray repair cross complementing 1 protein (XRCC1) and Fanconi anemia complementation group A protein (FANCA). Genotyping was conducted in 170 patients with Down syndrome AML or TMD, and 202 healthy blood donor controls. All genotype frequencies in the control populations were consistent with those expected from Hardy-Weinberg equilibrium. We found that the variant NQO1 Pro187Ser allele, associated with reduced quinone reductase activity, occurred with a greater frequency in the Down syndrome AML/TMD patient population compared to healthy controls (OR, 1.61; 95% CI, 1.067–2.426; p=0.0231). The FANCA-1501 variant allele frequency was observed more frequently in Down syndrome AML/TMD patients compared to healthy controls (OR, 1.77; 95%CI, 1.220–2.568; p=0.0025). The variant XRCC-1 Arg399Gln allele was observed less frequently in the TMD/DS AML population as compared to controls (OR, 0.536; CI, 0.354–0.811; p=0.0031). These latter findings parallel the observation of a protective effect against AML in non-Down syndrome individuals with at least one copy of the XRCC-1 Arg399Gln allele (Seedhouse et al. Blood2002, 100:3761). Conclusion: These preliminary studies, representing the only reported data in Down Syndrome TMD/AML patients, suggest that functional polymorphic variants of the NQO1, FANCA, and XRCC1 genes involved in oxidant metabolism and DNA repair may influence the risk for developing leukemia. Studies involving future cohorts will be needed to confirm these observations.

Immunophenotypic classification of leukemia has important therapeutic and prognostic implications. In B-cell malignancies, CD20 and CD22 also represent therapeutic targets. CD20 expression in adult patients with B lineage ALL has been associated with a poor prognosis. The data are conflicting in the pediatric population and may be impacted by the type of therapy employed. A recent study of pediatric patients treated in consecutive St Jude Children’s Research Hospital Total Therapy ALL regimens observed excellent outcomes and no prognostic significance for CD20 expression (Jeha et al. Blood2006, 108:3302–3304). We retrospectively analyzed 50 consecutive patients aged 4 months to 28 years with precursor-B ALL treated with contemporary risk-adapted BFM-based ALL regimens for whom flow cytometric, genetic, and early response data were available. Cases were defined as positive for CD20 and/or CD22 expression if surface expression was identified in more than 20% of leukemic blasts. We found that CD22 was expressed at high levels (68–99%) in all patients evaluated. CD20 expression was positive in 27 (54%) of patients. CD20 expression did not correlate with known NCI prognostic features, including presenting white blood count or age. All 3 patients with BCR-ABL translocation ALL were CD20 positive. Consistent with previously published data, neither of the 2 patients with MLL-AF4 translocation were CD20 positive. There was no association of CD20 expression with trisomy 4/10/17 or TEL-AML1 status. We did not observe an association between CD20 expression and rapid early bone marrow response to therapy at day 8 or 15; 47/50 patients were in remission at day 29. At a median follow-up time of 48 months 46/50 patients were alive without relapse. These limited data do not suggest a strong association between CD20 expression and known prognostic features or early treatment response in pediatric precursor-B ALL treated with contemporary BFM therapy platforms. However, our findings of frequent expression of CD22 on precursor-B ALL blasts from children supports its consideration as a target for immunotherapy approaches in high risk or relapsed disease.