AN OLIGOMER COMPLEMENTARY TO C-MYB-ENCODED MESSENGER-RNA INHIBITS PROLIFERATION OF HUMAN MYELOID-LEUKEMIA CELL-LINES
AN OLIGOMER COMPLEMENTARY TO C-MYB-ENCODED MESSENGER-RNA INHIBITS PROLIFERATION OF HUMAN MYELOID-LEUKEMIA CELL-LINES
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DOI：
10.1073/pnas.86.9.3379
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发表时间：
1989-05-01
影响因子：
11.1
通讯作者：
CALABRETTA, B
中科院分区：
文献类型：
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作者：
ANFOSSI, G;GEWIRTZ, AM;CALABRETTA, B
为了研究原癌基因c-myb在调节髓系白血病细胞增殖和分化中的作用，我们将人白血病细胞系HL-60、ML-3、KG-1和KG-1a暴露于与c-myb编码mRNA的18个碱基对（bp）序列互补的寡脱氧核苷酸。这种处理导致所有细胞系中细胞增殖的显著降低，这在HL-60细胞中最显著。培养5天后，在几个不同的寡聚体制剂的单独实验中，与未处理的HL-60细胞相比，在c-myb反义处理的细胞中观察到75%的生长抑制。两个c-myb反义寡聚体的长度相同，无论是2-或4-bp的错配没有影响细胞生长，也没有一个18 bp的c-myb正义或髓过氧化物酶反义寡聚体。还研究了c-myc反义寡聚体（18 bp）对HL-60、KG-1和KG-1a细胞生长的影响。该寡聚体对细胞增殖的抑制作用比c-myb反义序列小得多。有趣的是，尽管c-myc反义处理诱导HL-60细胞成熟，同时抑制细胞增殖，但在c-myb反义处理的细胞中没有观察到这种效果。这些研究表明，c-myb原癌基因编码的核蛋白是维持某些白血病细胞系增殖所必需的。此外，与c-myc蛋白相比，对c-myb蛋白的严格要求表明，至少在HL-60细胞中，c-myc扩增或N-ras活化可能不足以在不存在c-myb蛋白的情况下维持白血病生长。这些发现支持了恶性表型的发展和维持需要多种相互关联的遗传事件的假设。
To study the role of the protooncogene c-myb in regulating myeloid leukemia cell proliferation and differentiation, we exposed cells of the human leukemia lines HL-60, ML-3, KG-1, and KG-1a to an oligodeoxynucleotide complementary to an 18-base-pair (bp) sequence of c-myb-encoded mRNA. This treatment resulted in a significant decrease in cell proliferation in all of the lines, which was most marked in HL-60 cells. After 5 days in culture, in several separate experiments with different oligomer preparations, 75% growth inhibition was observed in c-myb antisense treated cells in comparison to untreated HL-60 cells. Two c-myb antisense oligomers of identical length with either 2- or 4-bp mismatches had no effect on cell growth nor did an 18-bp c-myb sense or myeloperoxidase antisense oligomer. The effect of a c-myc antisense oligomer (18 bp) on the growth of HL-60, KG-1, and KG-1a cells was also studied. This oligomer had much less inhibitory effect on cell proliferation than did the c-myb antisense sequence. Interestingly, although c-myc antisense treatment induced maturation of HL-60 cells while it inhibited cell proliferation, such an effect was not noted in c-myb antisense treated cells. These studies indicate that the nuclear protein encoded by the c-myb protooncogene is required for maintenance of proliferation in certain leukemia cell lines. In addition, the stringent requirements for c-myb protein as compared to c-myc protein suggest that, at least in HL-60 cells, c-myc amplification or N-ras activation may not be sufficient to maintain the leukemic growth in the absence of c-myb protein. These findings support the hypothesis that development and maintenance of a malignant phenotype requires a multiplicity of interrelated genetic events.