Interdisciplinary Training

Kim Robien

Folate status and risk of relapse following hematopoietic cell transplant for chronic myelogenous leukemia

The American Cancer Society estimates that 4,700 new cases of chronic myelogenous leukemia (CML) will be diagnosed in the United States in 2001. Allogeneic hematopoietic cell transplantation (HCT) is currently the only known curative therapy for CML, although the relapse rate is about 20%. Folate is an essential nutrient for nucleotide synthesis, and folate deficiency is associated with several measures of DNA damage. In CML patients undergoing HCT, several factors can affect folate status: genetic polymorphisms in folate metabolizing enzymes that affect function; dietary folate intake; supplement use; and the use of anti-folate medications (methotrexate [MTX] and trimethoprim/sulfamethoxazole [Bactrim]). As disease progression in CML has been associated with the accumulation of additional chromosome aberrations, we hypothesize that low folate status is associated with genetic instability that promotes an increased risk of reappearance of a malignant clone in a dormant disease. The aim of this study is to investigate the association between folate status and risk of relapse following HCT in patients with CML.

Folate is a B vitamin which acts as a carrier of single carbon fragments for transfer to various targets. Metabolic roles of folate that may be related to carcinogenesis include: 1) as a factor in DNA synthesis (thymidine and purine synthesis); and 2) as an essential cofactor for methylation reactions. Folate deficiency has been shown to result in uracil misincorporation into DNA strands during replication with subsequent increased double-strand DNA breaks during uracil excision repair. Thus, an inadequate folate status may be involved in cancer etiology. A low folate status has been found to be associated with an increased genetic instability and increased risk of developing several cancers, especially colorectal cancer. While previous research has investigated the role of folate status in the development of primary malignancies, this study will investigate whether folate status plays a role in the risk of relapse following HCT for CML.