Down syndrome, drug metabolism and chromosome 21.
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 is on account of increased intracellular transport of MTX via the reduced folate carrier (RFC) whose gene is localized to chromosome 21 and may also account for the increased MTX-associated toxicity of DS ALL patients. Microarray technology should lead to the identification of additional gene targets linked to the treatment response of specific cytogenetic leukemia subgroups.
Taub
Jeffrey W
JW
Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA. jtaub@med.wayne.edu
Ge
Yubin
Y
D000208:Acute Disease; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use*; D002648:Child; D002891:Chromosomes, Human, Pair 21; D018572:Disease-Free Survival; D004314:Down Syndrome / Q000150:complications* / Q000503:physiopathology; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy* / Q000235:genetics; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics; D008727:Methotrexate / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D011379:Prognosis
D018906:Antineoplastic Agents, Alkylating; D008727:Methotrexate