Influence of DNA Methylation and Core Binding Factors in Expression of Leukemia Virus in Hemapoietic Stem Cells

Abstract

Retroviral vectors based upon the Moloney murine leukemia virus (MLV) have been used due to their high efficiency of stable gene transfer. Core binding factors (CBF) are heterodimeric transcription factors containing a DNA binding Runx 1, Runx 2, or Runx 3 subunit, along with a non DNA binding CBF subunit. All four subunits are required at one or more stages of hematopoiesis. This review describes the role of Runx1 and CBF ß in the initiation of hematopoiesis in the embryo, and in the emergence of hematopoietic stem cells. The core site in the Moloney murine leukemia virus (Moloney MLV) enhancer was previously shown to be an important determinant of the T-cell disease specificity of the virus. Mutation of the core site resulted in a significant shift in disease specificity of the Moloney virus from T-cell leukemia to erythro-leukemia. It has been shown that a protein that binds the core site, one of the core-binding factors is highly expressed in thymus and is essential for hematopoiesis in stem cells. Earlier studies suggest that CBF plays a critical role in mediating pathogenesis of Moloney MLV in vivo. Spontaneous leukemia was not observed either upon CBF expression, consistent with a model in which the increase in HSC and progenitor populations represents a pre-leukemic state, and additional mutations are required for progression to leukemia.