Downregulating Notch counteracts Kras^G12D-induced ERK activation and oxidative phosphorylation in myeloproliferative neoplasm.

ABSTRACT: The Notch signaling pathway contributes to the pathogenesis of a wide spectrum of human cancers, including hematopoietic malignancies. Its functions are highly dependent on the specific cellular context. Gain-of-function NOTCH1 mutations are prevalent in human T-cell leukemia, while loss of Notch signaling is reported in myeloid leukemias. Here, we report a novel oncogenic function of Notch signaling in oncogenic Kras-induced myeloproliferative neoplasm (MPN). We find that downregulation of Notch signaling in hematopoietic cells via DNMAML expression or Pofut1 deletion significantly blocks MPN development in Kras^G12D mice in a cell-autonomous manner. Further mechanistic studies indicate that inhibition of Notch signaling upregulates Dusp1, a dual phosphatase that inactivates p-E

SUBMITTER: Kong G 

PROVIDER: S-EPMC6405304 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature