GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia.

Abstract

Down syndrome children with acute megakaryocytic leukemia (AMkL) have higher cure rates than non-Down syndrome acute myeloid leukemia (AML) patients treated with cytosine arabinoside (ara-C). Megakaryoblasts from Down syndrome AML patients are more sensitive in vitro to ara-C than cells from non-Down syndrome AML patients. Somatic mutations in the GATA1 transcription factor have been detected exclusively and almost uniformly in Down syndrome AMkL patients, suggesting a potential linkage to the chemotherapy sensitivity of Down syndrome megakaryoblasts. Stable transfection of wild-type GATA1 cDNA into the Down syndrome AMkL cell line CMK resulted in decreased (8- to 17-fold) ara-C sensitivity and a threefold-lower generation of the active ara-C metabolite ara-CTP compared with that for mock-transfected CMK cells. High intracellular levels of uridine arabinoside (ara-U) (an inactive ara-C catabolite generated by cytidine deaminase) and cytidine deaminase transcripts were detected in GATA1-transfected CMK sublines, whereas no ara-U was detected in mock-transfected cells. Cytidine deaminase transcripts were a median 5.1-fold (P = .002) lower in Down syndrome megakaryoblasts (n = 16) than in blast cells from non-Down syndrome patients (n = 56). These results suggest that GATA1 transcriptionally upregulates cytidine deaminase and that the presence or absence of GATA1 mutations in AML blasts likely confers differences in ara-C sensitivities due to effects on cytidine deaminase gene expression, which, in turn, contributes to the high cure rate of Down syndrome AMkL patients.

• Authors: Yubin Ge, Mark L Stout, Dana A Tatman, Tanya L Jensen, Steven Buck, Ronald L Thomas, Yaddanapudi Ravindranath, Larry H Matherly, Jeffrey W Taub
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 97 Issue 3 Pg. 226-31 (Feb 02 2005) ISSN: 1460-2105 [Electronic] United States
• PMID: 15687366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antimetabolites, Antineoplastic
• DNA-Binding Proteins
• Erythroid-Specific DNA-Binding Factors
• GATA1 Transcription Factor
• GATA1 protein, human
• Transcription Factors
• Cytarabine
• Arabinofuranosylcytosine Triphosphate
• Arabinofuranosyluracil
• Cytidine Deaminase

Topics

• Antimetabolites, Antineoplastic (metabolism)
• Arabinofuranosylcytosine Triphosphate (metabolism)
• Arabinofuranosyluracil (metabolism)
• Blotting, Western
• Child
• Cytarabine (metabolism)
• Cytidine Deaminase (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Down Syndrome (complications, genetics, metabolism)
• Erythroid-Specific DNA-Binding Factors
• GATA1 Transcription Factor
• Humans
• Leukemia, Megakaryoblastic, Acute (complications, enzymology, genetics, metabolism)
• Polymerase Chain Reaction
• Time Factors
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic
• Transcriptional Activation
• Up-Regulation