Synergistic Induction of T Cell Acute Lymphoblastic Leukemia by Functionally Distinct Mutations in NOTCH1.

Recent observations that Notch1 mutations are present in more than 50% of human T-ALL patient samples indicate that Notch signals have a central role in the pathogenesis of T-ALL (Weng et al., 2004, Science, 306, 269–271). Notch1 mutations are of two types: i) mis-sense mutations in an extracellular heterodimerization (HD) domain; and ii) frameshift or stop codon mutations that result in deletion of an intracellular PEST destruction box. The likely effect(s) of these mutations is to i) cause heightened proteolytic activation of Notch1, an event that requires the enzyme gamma-secretase; and to ii) increase the duration of Notch1 signaling, respectively. To investigate the contribution of the HD and PEST domain mutations to the pathogenesis of human T-ALL, Notch1 alleles with common HD mutations were introduced retrovirally into hematopoietic progenitor cells, which were then transplanted into lethally irradiated mice. These mice developed transiently circulating abnormal CD4⁺CD8⁺ T cells, but failed to develop leukemia after 9 months of monitoring. Similar findings occurred when Notch1 alleles bearing only PEST mutations were introduced into mice, as previously noted by others (