Down syndrome, drug metabolism and chromosome 21

Pediatric Blood & Cancer
Jeffrey W Taub, Yubin Ge

Abstract

It has been recognized that chromosomal abnormalities in childhood leukemia, are linked to both leukemogenesis and segregate patients into prognostic treatment groups. This is best exemplified in cases of children with Down syndrome (DS), who have significantly higher risks of developing leukemia compared to non-DS children and distinctive treatment outcomes, particularly in cases of acute myeloid leukemia (AML). The high event-free survival (EFS) rates of DS AML patients and in particular, patients with megakaryocytic leukemia (AMkL), at least in part reflects an increased sensitivity to cytosine arabinoside (ara-C) secondary to increased expression of the chromosome 21-localized gene, cystathionine-beta-synthase, and potentially global mechanisms which increase the susceptibility of cells to undergo apoptosis. Somatic mutations of the X-linked transcription factor gene, GATA1, have been detected uniformly and exclusively in DS AMkL cases, which may lead to altered expression of GATA1 target genes and alter the metabolism of drugs including ara-C. Hyperdiploid acute lymphoblastic leukemia (ALL) cells with extra copies of chromosome 21, generate higher levels of the active methotrexate (MTX) metabolite, MTX polyglutamates. This...Continue Reading

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