| Autor: |
Ge, Yubin, Stout, Mark L., Tatman, Dana A., Jensen, Tanya L., Buck, Steven A., Thomas, Ronald L., Ravindranath, Yaddanapudi, Matherly, Larry H., Taub, Jeffrey W. |
| Předmět: |
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| Zdroj: |
JNCI: Journal of the National Cancer Institute; 2/2/2005, Vol. 97 Issue 3, p226-231, 6p, 1 Chart, 3 Graphs |
| Abstrakt: |
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 GATAI 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 eDNA 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 deamlnase) and cytidme deammase 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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