GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia.
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.
Ge
Yubin
Y
Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
Stout
Mark L
ML
Tatman
Dana A
DA
Jensen
Tanya L
TL
Buck
Steven
S
Thomas
Ronald L
RL
Ravindranath
Yaddanapudi
Y
Matherly
Larry H
LH
Taub
Jeffrey W
JW
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001086:Arabinofuranosyluracil / Q000378:metabolism; D015153:Blotting, Western; D002648:Child; D003561:Cytarabine / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D014157:Transcription Factors; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D001086:Arabinofuranosyluracil; D003564:Cytidine Deaminase