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

Guangyao Kong*, Xiaona You, Zhi Wen, Yuan I. Chang, Shuiming Qian, Erik A. Ranheim, Christopher Letson, Xinmin Zhang, Yun Zhou, Yangang Liu, Adhithi Rajagopalan, Jingfang Zhang, Elliot Stieglitz, Mignon Loh, Inga Hofmann, David Yang, Xuehua Zhong, Eric Padron, Lan Zhou, Warren S. PearJing Zhang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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-ERK, and downregulates cytokine-evoked ERK activation in Kras G12D cells. Moreover, mitochondrial metabolism is greatly enhanced in Kras G12D cells but significantly reprogrammed by DNMAML close to that in control cells. Consequently, cell proliferation and expanded myeloid compartment in Kras G12D mice are significantly reduced. Consistent with these findings, combined inhibition of the MEK/ERK pathway and mitochondrial oxidative phosphorylation effectively inhibited the growth of human and mouse leukemia cells in vitro. Our study provides a strong rational to target both ERK signaling and aberrant metabolism in oncogenic Ras-driven myeloid leukemia.

Original languageEnglish
Pages (from-to)671-685
Number of pages15
JournalLeukemia
Volume33
Issue number3
DOIs
StatePublished - 1 Mar 2019

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