Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice

Blood. 2009 Apr 2;113(14):3323-32. doi: 10.1182/blood-2008-06-162248. Epub 2009 Jan 28.

Abstract

The core-binding factor (CBF) is a master regulator of developmental and differentiation programs, and CBF alterations are frequently associated with acute leukemia. The role of the CBF member RUNX2 in hematopoiesis is poorly understood. Genetic evidence suggests that deregulation of Runx2 may cause myeloid leukemia in mice expressing the fusion oncogene Cbfb-MYH11. In this study, we show that sustained expression of Runx2 modulates Cbfbeta-smooth muscle myosin heavy chain (SMMHC)-mediated myeloid leukemia development. Expression of Runx2 is high in the hematopoietic stem cell compartment and decreases during myeloid differentiation. Sustained Runx2 expression hinders myeloid progenitor differentiation capacity and represses expression of CBF targets Csf1R, Mpo, Cebpd, the cell cycle inhibitor Cdkn1a, and myeloid markers Cebpa and Gfi1. In addition, full-length Runx2 cooperates with Cbfbeta-SMMHC in leukemia development in transplantation assays. Furthermore, we show that the nuclear matrix-targeting signal and DNA-binding runt-homology domain of Runx2 are essential for its leukemogenic activity. Conversely, Runx2 haplo-insufficiency delays the onset and reduces the incidence of acute myeloid leukemia. Together, these results indicate that Runx2 is expressed in the stem cell compartment, interferes with differentiation and represses CBF targets in the myeloid compartment, and modulates the leukemogenic function of Cbfbeta-SMMHC in mouse leukemia.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow / metabolism
  • Bone Marrow / physiology
  • Cell Differentiation / genetics
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Core Binding Factor Alpha 1 Subunit / physiology*
  • Down-Regulation / genetics
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / physiology
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / mortality
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / physiology*
  • Survival Analysis

Substances

  • CBFbeta-MYH11 fusion protein
  • Core Binding Factor Alpha 1 Subunit
  • Oncogene Proteins, Fusion
  • Runx2 protein, mouse