table_1_NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells.PDF

To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs). In NOTCH1-mutated CLL, we detected subclonal mutations in 57% CD34+/CD38− HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38− and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.

为研究慢性淋巴细胞白血病（chronic lymphocytic leukemia, CLL）起始细胞，我们对造血干细胞（hematopoietic stem cells, HSCs）中的NOTCH1突变与表达情况进行了评估。在携带NOTCH1突变的CLL患者中，我们在57%的CD34+/CD38−造血干细胞中检测到了亚克隆突变。相较于造血干细胞，66%的CD34+/CD38+祖细胞中存在NOTCH1突变，且其突变负荷更高。流式细胞术分析显示，无论是否携带NOTCH1突变，CLL患者的CD34+/CD38−与CD34+/CD38+细胞中的NOTCH1激活水平均显著高于健康供者。激活的NOTCH1可导致其靶基因c-MYC的过表达。综上，我们认为激活的NOTCH1是CLL发生中的早期事件，可能参与了该疾病中异常造血干细胞的形成。