GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia
GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia
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DOI：
10.1093/jnci/dji026
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发表时间：
2005-02-02
影响因子：
10.3
通讯作者：
Taub, JW
中科院分区：
文献类型：
--
作者：
Ge, YB;Stout, ML;Taub, JW
患有唐氏综合征的急性巨核细胞白血病（AMkL）患儿的治愈率高于接受阿糖胞苷（ara-C）治疗的非唐氏综合征急性髓细胞白血病（AML）患者。来自唐氏综合征AML患者的巨核母细胞在体外对阿糖胞苷比来自非唐氏综合征AML患者的细胞更敏感。GATA 1转录因子的体细胞突变在唐氏综合征AMkL患者中几乎一致地被检测到，这表明唐氏综合征巨核细胞的化疗敏感性存在潜在的联系。野生型GATA 1 cDNA稳定转染到唐氏综合征AMkL细胞系CMK导致降低（8- 17倍）阿糖胞苷的敏感性和三倍低代的活性阿糖胞苷代谢产物阿糖胞苷CTP相比，模拟转染CMK细胞。在GATA 1转染的CMK亚系中检测到高细胞内水平的尿苷阿拉伯糖苷（ara-U）（一种由胞苷脱氨酶产生的无活性ara-C分解代谢产物）和胞苷脱氨酶转录物，而在模拟转染的细胞中未检测到ara-U。唐氏综合征巨核母细胞（n = 16）中的胞苷脱氨酶转录物中位数比非唐氏综合征患者（n = 56）的原始细胞低5.1倍（P = 0.002）。这些结果表明，GATA 1转录上调胞苷脱氨酶，AML母细胞中存在或不存在GATA 1突变可能会由于对胞苷脱氨酶基因表达的影响而导致araC敏感性的差异，这反过来又有助于唐氏综合征AMkL患者的高治愈率。
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 araC sensitivities due to effects on cytidine deaminase gene expression, which, in turn, contributes to the high cure rate of Down syndrome AMkL patients.