Mutant RAS inhibits neutrophil but not macrophage differentiation and allows continued growth of neutrophil precursors
Mutant RAS inhibits neutrophil but not macrophage differentiation and allows continued growth of neutrophil precursors
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DOI：
10.1016/s0301-472x(99)00100-9
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发表时间：
1999-11-01
影响因子：
2.6
通讯作者：
Burnett, AK
中科院分区：
文献类型：
--
作者：
Darley, RL;Burnett, AK
RAS突变激活是髓系白血病中最常见的分子异常。为了更好地了解其在白血病发生中的作用，我们设计了一个基于多能细胞系FDCP混合物的模型。我们表明，突变RAS在FDCP-混合物中的表达强烈抑制终末中性粒细胞分化的影响下，G-CSF加GM-CSP在晚幼粒细胞阶段，而巨噬细胞分化不受影响。此外，而对照培养物分化，并成为有丝分裂后在这些条件下，FDCP-混合物细胞表达突变RAS继续无限增殖，同时保持晚幼粒细胞表型。用荧光示踪染料PKH 26标记这些培养物，表明这种延长的增殖能力是由于培养物中晚幼粒细胞的持续分裂。对这些细胞的生长因子反应的分析表明，GM-CSF在维持这些细胞的增殖和抑制其分化方面是关键的。我们进一步表明，用低剂量Ara C处理可以部分克服中性粒细胞分化的阻滞，这表明维持细胞周期进程可能是该癌基因的抗分化作用的部分原因。这些发现表明RAS的激活能够特异性抑制终末中性粒细胞分化，并且这样做促进晚幼粒细胞的持续分裂，（C）1999 International Society for Experimental Hematology。出版社：Elsevier Science Inc.
Mutational activation of RAS is the most common molecular abnormality in myeloid leukemias. In order to better understand its role in leukemogenesis, we have devised a model based on the multipotent cell line, FDCP-mix. We show that expression of mutant RAS in FDCP-mix strongly inhibits terminal neutrophil differentiation under the influence of G-CSF plus GM-CSP at the metamyelocyte stage, whereas macrophage differentiation was unaffected, In addition, whereas control cultures differentiated and became postmitotic under these conditions, FDCP-mix cells expressing mutant RAS continued to proliferate indefinitely while maintaining a metamyelocytic phenotype. Labeling of these cultures with the fluorescent tracking dye, PKH26, showed that this extended proliferative capacity resulted from continued division of metamyelocytes in the culture. Dissection of the growth factor response of these cells demonstrated that GM-CSF was critical in maintaining proliferation and inhibiting the differentiation of these cells, We further show the block in neutrophil differentiation could be partially overcome by treatment with low-dose Ara C, suggesting that maintenance of cell cycle progression may be partly responsible for the anti-differentiation effect of this oncogene, These findings suggest that activation of RAS is able to specifically inhibit terminal neutrophil differentiation and in so doing promotes continued division of metamyelocyte cells, (C) 1999 International Society for Experimental Hematology. Published by Elsevier Science Inc.