MUTATIONS IN THE GENE FOR THE GRANULOCYTE COLONY-STIMULATING-FACTOR RECEPTOR IN PATIENTS WITH ACUTE MYELOID-LEUKEMIA PRECEDED BY SEVERE CONGENITAL NEUTROPENIA
MUTATIONS IN THE GENE FOR THE GRANULOCYTE COLONY-STIMULATING-FACTOR RECEPTOR IN PATIENTS WITH ACUTE MYELOID-LEUKEMIA PRECEDED BY SEVERE CONGENITAL NEUTROPENIA
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DOI：
10.1056/nejm199508243330804
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发表时间：
1995-08-24
影响因子：
158.5
通讯作者：
TOUW, IP
中科院分区：
文献类型：
--
作者：
DONG, F;BRYNES, RK;TOUW, IP
背景资料。在严重先天性中性粒细胞减少症中，髓系祖细胞成熟受阻，部分严重先天性中性粒细胞减少症患者出现骨髓增生异常综合征和急性髓系白血病，粒细胞集落刺激因子(G-CSF)信号转导通路异常可能参与了急性髓系白血病的进展。我们从两名有严重先天性中性粒细胞减少史的急性髓系白血病患者的造血细胞中分离出基因组DNA和RNA。用聚合酶链式反应扩增G-CSF受体胞浆区的核苷酸序列并测序，将编码野生型和突变型G-CSF受体的互补DNA导入小鼠髓系32D.C10细胞，检测其对G-CSF的反应。在这两个患者中都发现了G-CSF受体基因的点突变。这些突变，一名患者在718位密码子上用胸腺嘧啶取代胞嘧啶取代谷氨酰胺(Gln718)，另一位患者在731位密码子(Gln731)用胸腺嘧啶取代胞嘧啶，导致受体的C末端细胞质区域被截断。两名患者的白血病细胞中均存在G-CSF受体的突变型和野生型基因，其中一名患者在发展为急性髓系白血病之前的中性粒细胞减少期也发现了突变。表达突变受体的32D.C10细胞具有异常高的增殖反应，但在G-CSF培养下未能成熟。在共表达野生型和突变型受体的32D.C10细胞中，突变型G-CSF受体还干扰野生型G-CSF受体介导的终末成熟。G-CSF受体基因突变干扰了髓系细胞成熟所需的信号，参与了严重先天性中性粒细胞减少症的发病机制，并与急性髓系白血病的进展有关。
Background. In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested, The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia, Abnormalities in the signal-transduction pathways for granulocyte colony-stimulating factor (G-CSF) may play a part in the progression to acute myeloid leukemia.Methods. We isolated genomic DNA and RNA from hematopoietic cells obtained from two patients with acute myeloid leukemia and histories of severe congenital neutropenia. The nucleotide sequences encoding the cytoplasmic domain of the G-CSF receptor were amplified by means of the polymerase chain reaction and sequenced, Murine myeloid 32D.C10 cells were transfected with complementary DNA encoding the wild-type or mutant G-CSF receptors and tested for their responses to G-CSF.Results. Point mutations in the gene for the G-CSF receptor were identified in both patients. The mutations, a substitution of thymine for cytosine at the codon for glutamine at position 718 (Gln718) in one patient and at the codon for glutamine at position 731 (Gln731) in the other, caused a truncation of the C-terminal cytoplasmic region of the receptor. Both mutant and wild-type genes for the G-CSF receptor were present in leukemic cells from the two patients, in one patient, the mutation was also found in the neutropenic stage, before the progression to acute myeloid leukemia. The 32D.C10 cells expressing mutant receptors had abnormally high proliferative responses but failed to mature when cultured in G-CSF. The mutant G-CSF receptors also interfered with terminal maturation mediated by the wild-type G-CSF receptor in the 32D.C10 cells that coexpressed the wildtype and mutant receptors.Conclusions. Mutations in the gene for the G-CSF receptor that interrupt signals required for the maturation of myeloid cells are involved in the pathogenesis of severe congenital neutropenia and associated with the progression to acute myeloid leukemia.