AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway

Blood. 2013 Jun 13;121(24):4906-16. doi: 10.1182/blood-2012-08-447763. Epub 2013 May 3.

Abstract

Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and β-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. Inhibition of COX suppresses β-catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of β-catenin also abrogates the clonogenic growth of AE(+) mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/β-catenin-dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments.

Publication types

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

MeSH terms

  • Animals
  • Cell Proliferation*
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism*
  • Cyclooxygenase 2 / biosynthesis*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase Inhibitors / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Gene Expression Regulation, Leukemic / drug effects
  • Gene Expression Regulation, Leukemic / genetics
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • K562 Cells
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • RUNX1 Translocation Partner 1 Protein
  • Signal Transduction*
  • Sulfonamides / pharmacology
  • Transplantation, Heterologous
  • Zebrafish
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • Cyclooxygenase Inhibitors
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein
  • Sulfonamides
  • beta Catenin
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • nimesulide