Germeshausen Manuela, Ballmaier Matthias, Welte Karl
Department of Pediatric Hematology and Oncology, Hannover Medical School, Germany.
Blood. 2007 Jan 1;109(1):93-9. doi: 10.1182/blood-2006-02-004275. Epub 2006 Sep 19.
Point mutations in the gene for the granulocyte colony-stimulating factor (G-CSF) receptor CSF3R have been implicated in the progression of severe congenital neutropenia (CN) to leukemia. In this study we present data on a total of 218 patients with chronic neutropenia, including 148 patients with CN (23/148 with secondary malignancies). We detected CSF3R nonsense mutations at 17 different nucleotide positions (thereof 10 new mutations) which lead to a loss of 1 to all 4 tyrosine residues in the intracellular domain of the receptor. Of 23 patients with CN with signs of malignant transformation, 18 (78%) were shown to harbor a CSF3R mutation, indicating that these mutations, although not a necessary condition, are highly predictive for malignant transformation even if detected in a low percentage of transcripts. In serial analyses of 50 patients with CSF3R mutations we were able to follow the clonal dynamics of mutated cells. We could demonstrate that even a highly clonal hematopoiesis did not inevitably show a rapid progression to leukemia. Our results strongly suggest that acquisition of a CSF3R mutation is an early event in leukemogenesis that has to be accompanied by cooperating molecular events, which remain to be defined.
粒细胞集落刺激因子（G-CSF）受体CSF3R基因中的点突变与严重先天性中性粒细胞减少症（CN）进展为白血病有关。在本研究中，我们展示了总共218例慢性中性粒细胞减少症患者的数据，其中包括148例CN患者（148例中有23例发生继发性恶性肿瘤）。我们在17个不同的核苷酸位置检测到CSF3R无义突变（其中10个为新突变），这些突变导致受体胞内结构域中1至全部4个酪氨酸残基缺失。在23例有恶性转化迹象的CN患者中，18例（78%）被证明存在CSF3R突变，这表明这些突变虽然不是必要条件，但即使在低比例的转录本中检测到，也对恶性转化具有高度预测性。在对50例有CSF3R突变患者的系列分析中，我们能够追踪突变细胞的克隆动态。我们可以证明，即使是高度克隆性造血也不一定会迅速进展为白血病。我们的结果强烈表明，获得CSF3R突变是白血病发生过程中的一个早期事件，必须伴有协同的分子事件，而这些事件仍有待确定。
