Immunology Department, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
Leuk Res. 2011 Nov;35(11):1512-9. doi: 10.1016/j.leukres.2011.07.024. Epub 2011 Aug 15.
To understand the interactions between Notch1 and Ikaros in the evolution of T cell acute lymphoblastic leukemia (T-ALL), we traced the evolution of T-ALL in mice with an inherited Ikaros mutation, Ikzf1(Plstc) which inactivates DNA binding. DNA-binding Ikaros repressed Notch1 response in transfected cell lines and in CD4(+)8(+) (DP) thymocytes from young pre-leukemic Ikzf1(Plstc) heterozygous mice. In DP thymocytes, a 50-1000 fold escalation in mRNA for Notch1 target genes Hes1 and Dtx1 preceded thymic lymphoma or leukemia and was closely correlated with the first detectable differentiation abnormalities, loss of heterozygosity (LOH) eliminating wild-type Ikzf1, and multiple missense and truncating Notch1 mutations. These findings illuminate the early stages of leukemogenesis by demonstrating progressive exaggeration of Notch1 responsiveness at the DP thymocyte stage brought about by multiple mutations acting in concert upon the Notch1 pathway.
为了理解 Notch1 和 Ikaros 在 T 细胞急性淋巴细胞白血病（T-ALL）中的相互作用，我们追踪了具有遗传性 Ikaros 突变（Ikzf1(Plstc)）的小鼠中 T-ALL 的进化，该突变使 DNA 结合失活。DNA 结合的 Ikaros 抑制了转染细胞系和来自年轻前白血病 Ikzf1(Plstc)杂合子小鼠的 CD4(+)8(+) (DP)胸腺细胞中的 Notch1 反应。在 DP 胸腺细胞中，Notch1 靶基因 Hes1 和 Dtx1 的 mRNA 水平升高了 50-1000 倍，随后发生了胸腺淋巴瘤或白血病，并且与最初可检测到的分化异常、消除野生型 Ikzf1 的杂合性丢失（LOH）以及多种错义和截断的 Notch1 突变密切相关。这些发现通过证明 Notch1 通路的多种突变协同作用导致 DP 胸腺细胞阶段 Notch1 反应逐渐增强，阐明了白血病发生的早期阶段。
