Dong F, Brynes R K, Tidow N, Welte K, Löwenberg B, Touw I P
Department of Hematology, Dr. Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
N Engl J Med. 1995 Aug 24;333(8):487-93. doi: 10.1056/NEJM199508243330804.
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.
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.
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 wild-type and mutant receptors.
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.
在严重先天性中性粒细胞减少症中，髓系祖细胞的成熟被阻断。一些严重先天性中性粒细胞减少症患者会发生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）信号转导途径的异常可能在进展为急性髓系白血病过程中起作用。
我们从两名患有急性髓系白血病且有严重先天性中性粒细胞减少症病史的患者的造血细胞中分离出基因组DNA和RNA。通过聚合酶链反应扩增编码G-CSF受体胞质结构域的核苷酸序列并进行测序。用编码野生型或突变型G-CSF受体的互补DNA转染小鼠髓系32D.C10细胞，并检测它们对G-CSF的反应。
在两名患者中均发现了G-CSF受体基因的点突变。其中一名患者在第718位谷氨酰胺密码子（Gln718）处发生胞嘧啶被胸腺嘧啶替代的突变，另一名患者在第731位谷氨酰胺密码子（Gln731）处发生同样的突变，这些突变导致受体C端胞质区域截短突变型和野生型G-CSF受体基因均存在于两名患者的白血病细胞中。在一名患者中，在进展为急性髓系白血病之前的中性粒细胞减少阶段也发现了该突变。表达突变型受体的32D.C10细胞具有异常高的增殖反应，但在G-CSF中培养时未能成熟。突变型G-CSF受体还在共表达野生型和突变型受体的32D.C10细胞中干扰了由野生型G-CSF受体介导的终末成熟。
G-CSF受体基因中的突变中断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，并与进展为急性髓系白血病相关。
