The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia

Blood. 2017 Jan 26;129(4):497-508. doi: 10.1182/blood-2016-05-714493. Epub 2016 Oct 18.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale short hairpin RNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation. To validate the in vivo relevance of genetic dependencies observed in human cell lines, we performed a secondary screen in a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein. Integrating the results of these interference RNA screens and additional gene expression data, we identified the transcription factor ZEB2 as a novel AML dependency. ZEB2 depletion impaired the proliferation of both human and mouse AML cells and resulted in aberrant differentiation of human AML cells. Mechanistically, we showed that ZEB2 transcriptionally represses genes that regulate myeloid differentiation, including genes involved in cell adhesion and migration. In addition, we found that epigenetic silencing of the miR-200 family microRNAs affects ZEB2 expression. Our results extend the role of ZEB2 beyond regulating epithelial-mesenchymal transition (EMT) and establish ZEB2 as a novel regulator of AML proliferation and differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Movement
  • Epigenesis, Genetic
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Transcription, Genetic
  • Zinc Finger E-box Binding Homeobox 2

Substances

  • Homeodomain Proteins
  • MIRN200 microRNA, human
  • MLL-AF9 fusion protein, mouse
  • MicroRNAs
  • Mirn200 microRNA, mouse
  • Oncogene Proteins, Fusion
  • RNA, Small Interfering
  • Repressor Proteins
  • ZEB2 protein, human
  • ZEB2 protein, mouse
  • Zinc Finger E-box Binding Homeobox 2