Mtg16 Variants Provide Context To Notch Signaling To Direct Leukemic Phenotype

Notch signaling guides hematopoietic stem and progenitor cells (HS/PCs) toward distinct cell fates and when dysfunctional, contributes to development of hematopoietic malignancies. Normally, Notch signaling favors T-cell fate and causes attenuated expression of myeloid-specific genes. In contrast, Notch pathway inactivation causes HS/PCs to diverge disproportionately toward a myeloid fate and is accompanied by T-lymphopenia. Mutations that constitutively activate Notch signaling trigger T-cell leukemia, while Notch inactivation is associated with myeloid leukemias. This suggests that Notch-regulated cell fate decisions are context dependent and that determinants downstream of Notch can influence Notch-dependent phenotypes in development and disease.