O'Neil Jennifer, Calvo Jennifer, McKenna Keith, Krishnamoorthy Veena, Aster Jon C, Bassing Craig H, Alt Frederick W, Kelliher Michelle, Look A Thomas
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Blood. 2006 Jan 15;107(2):781-5. doi: 10.1182/blood-2005-06-2553. Epub 2005 Sep 15.
Recent studies have demonstrated that most patients with T-cell acute lymphocytic leukemia (T-ALL) have activating mutations in NOTCH1. We sought to determine whether these mutations are also acquired in mouse models of T-ALL. We sequenced the heterodimerization domain and the PEST domain of Notch1 in our mouse model of TAL1-induced leukemia and found that 74% of the tumors harbor activating mutations in Notch1. Cell lines derived from these tumors undergo G(0)/G(1) arrest and apoptosis when treated with a gamma-secretase inhibitor. In addition, we found activating Notch1 mutations in 31% of thymic lymphomas that occur in mice deficient for various combinations of the H2AX, Tp53, and Rag2 genes. Thus, Notch1 mutations are often acquired as a part of the molecular pathogenesis of T-ALLs that develop in mice with known predisposing genetic alterations.
近期研究表明，大多数T细胞急性淋巴细胞白血病（T-ALL）患者的NOTCH1存在激活突变。我们试图确定在T-ALL小鼠模型中是否也会出现这些突变。我们对TAL1诱导的白血病小鼠模型中的Notch1异二聚化结构域和PEST结构域进行了测序，发现74%的肿瘤中Notch1存在激活突变。用γ-分泌酶抑制剂处理源自这些肿瘤的细胞系时，细胞会发生G(0)/G(1)期阻滞并凋亡。此外，我们在因H2AX、Tp53和Rag2基因各种组合缺陷的小鼠中发生的31%的胸腺淋巴瘤中发现了激活的Notch1突变。因此，Notch1突变常作为具有已知遗传易感性的小鼠发生T-ALL分子发病机制的一部分而出现。
