REGULATION OF C-MYC EXPRESSION DURING GROWTH AND DIFFERENTIATION OF NORMAL AND LEUKEMIC HUMAN MYELOID PROGENITOR CELLS
REGULATION OF C-MYC EXPRESSION DURING GROWTH AND DIFFERENTIATION OF NORMAL AND LEUKEMIC HUMAN MYELOID PROGENITOR CELLS
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DOI：
10.1172/jci112287
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发表时间：
1986-01-01
影响因子：
15.9
通讯作者：
BAGBY, GC
中科院分区：
文献类型：
--
作者：
GOWDA, SD;KOLER, RD;BAGBY, GC
从连续收获的集落刺激活性(CsA)刺激的正常祖细胞富集人骨髓细胞中获得的c-myc原癌基因转录产物与早幼粒细胞白血病细胞系HL-60和新鲜获得的人髓系白血病细胞的c-myc原癌基因转录产物进行了比较。在早期培养阶段，正常细胞和白血病细胞都表达c-myc癌基因。在正常细胞中，最高表达出现在培养24小时后，在没有CsA的情况下不会出现。此时，培养的细胞中以前粒细胞为主。虽然细胞在体外增殖96h，但c-myc的表达在24-36h后停止。在培养120h时，终末分化细胞占主导地位。相反，尽管白血病细胞在体外也表达c-myc，但转录在整个培养过程中一直存在，对于HL-60细胞，在没有外源CsA的情况下，转录发生了。我们还注意到，只有一个二倍体基因拷贝的正常细胞在培养24小时后，其转录本仅比HL-60细胞少两倍，而HL-60细胞中有16个myc拷贝。此外，c-myc基因在正常细胞和HL-60细胞中的降解率相似。我们的结论是，c-myc转录在粒细胞生成过程中是一种正常事件，与增殖活性有关，也与原始发育阶段有关。此外，白血病细胞在体外最一致的异常是它们未能抑制该基因的转录活性。我们认为，c-myc在HL-60细胞中的转录可能适合于处于发育停滞阶段的细胞，并且HL-60细胞中扩增的基因相对于同一分化阶段的正常细胞中的c-myc是静止的。在此描述的技术可能在鉴定正常的造血细胞抑制c-myc表达的机制和白血病细胞中这些机制的异常方面有价值。
C-myc proto-oncogene transcripts from serially harvested, colony-stimulating activity (CSA)-stimulated, normal progenitor-enriched human bone marrow cells were compared to those of the promyelocytic leukemia cell line HL-60 and to those of freshly obtained human myeloid leukemic cells. During the early culture period both normal and leukemic cells expressed the c-myc oncogene. In normal cells maximal expression occurred after 24 h of culture and did not occur in the absence of CSA. At this time, progranulocytes predominated in the cultured cells. Although cellular proliferation occurred for 96 h in vitro, c-myc expression ceased after 24-36 h. Terminally differentiated cells predominated in these cultures by 120 h. In contrast, although leukemic cells also expressed c-myc in vitro, transcription persisted thoughout the culture period and, in the case of HL-60 cells, occurred in the absence of exogenous CSA. We also noted that normal cells with only one diploid gene copy exhibited, after 24 h of culture, only twofold fewer transcripts than did HL-60 cells in which there were 16 myc copies. Furthermore, c-myc mRNA degradation rates were similar in normal cells and in HL-60 cells. We conclude that c-myc transcription is a normal event in granulopoiesis linked to proliferative activity as well as to primitive developmental stage. Furthermore, the most consistent abnormality in leukemic cells in vitro is their failure to suppress transcriptional activity of this gene. We suggest that c-myc transcription in HL-60 cells may be appropriate for cells arrested at that developmental stage and that the amplified genes in HL-60 cells are quiescent relative to c-myc in normal cells at the same differentiation stage. The techniques described herein may be of value in identifying mechanisms by which normal hematopoietic cells suppress c-myc expression and aberrancies of these mechanisms in leukemic cells.