Effects of notch signaling on regulation of myeloid cell differentiation in cancer

Pingyan Cheng, Vinit Kumar, Hao Liu, Je In Youn, Mayer Fishman, Simon Sherman, Dmitry Gabrilovich

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Functionally altered myeloid cells play an important role in immune suppression in cancer, in angiogenesis, and in tumor cells' invasion and metastases. Here, we report that inhibition of Notch signaling in hematopoietic progenitor cells (HPC), myeloid-derived suppressor cells (MDSC), and dendritic cells is directly involved in abnormal myeloid cell differentiation in cancer. Inhibition of Notch signaling was caused by the disruption of the interaction between Notch receptor and transcriptional repressor CSL, which is normally required for efficient transcription of target genes. This disruption was the result of serine phosphorylation of Notch. We demonstrated that increased activity of casein kinase 2 (CK2) observed in HPC and in MDSC could be responsible for the phosphorylation of Notch and downregulation of Notch signaling. Inhibition of CK2 by siRNA or by pharmacological inhibitor restored Notch signaling in myeloid cells and substantially improved their differentiation, both in vitro and in vivo. This study demonstrates a novel mechanism regulation of Notch signaling in cancer. This may suggest a new perspective for pharmacological regulation of differentiation of myeloid cells in cancer.

Original languageEnglish (US)
Pages (from-to)141-152
Number of pages12
JournalCancer Research
Volume74
Issue number1
DOIs
StatePublished - Jan 1 2014

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Myeloid Cells
Cell Differentiation
Casein Kinase II
Neoplasms
Hematopoietic Stem Cells
Phosphorylation
Pharmacology
Notch Receptors
Dendritic Cells
Serine
Small Interfering RNA
Down-Regulation
Neoplasm Metastasis
Genes
Myeloid-Derived Suppressor Cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Effects of notch signaling on regulation of myeloid cell differentiation in cancer. / Cheng, Pingyan; Kumar, Vinit; Liu, Hao; Youn, Je In; Fishman, Mayer; Sherman, Simon; Gabrilovich, Dmitry.

In: Cancer Research, Vol. 74, No. 1, 01.01.2014, p. 141-152.

Research output: Contribution to journalArticle

Cheng, P, Kumar, V, Liu, H, Youn, JI, Fishman, M, Sherman, S & Gabrilovich, D 2014, 'Effects of notch signaling on regulation of myeloid cell differentiation in cancer', Cancer Research, vol. 74, no. 1, pp. 141-152. https://doi.org/10.1158/0008-5472.CAN-13-1686
Cheng, Pingyan ; Kumar, Vinit ; Liu, Hao ; Youn, Je In ; Fishman, Mayer ; Sherman, Simon ; Gabrilovich, Dmitry. / Effects of notch signaling on regulation of myeloid cell differentiation in cancer. In: Cancer Research. 2014 ; Vol. 74, No. 1. pp. 141-152.
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