Elevated c-Jun expression in acute myeloid leukemias inhibits C/EBPα DNA binding via leucine zipper domain interaction

Abstract

Transcription factor C/EBPα induces normal myeloid differentiation, inactivation of C/EBPα leads to a differentiation block in acute myeloid leukemias (AML), and overexpression of C/EBPα results in AML growth arrest and differentiation. Recent reports suggest that C/EBPα is activated or inactivated via protein-protein interactions. We previously reported that C/EBPα needs to inactivate the proto-oncogene c-Jun via leucine zipper domain interaction in order to induce granulocytic differentiation. We, therefore, hypothesized that c-Jun expression might be elevated in AML and subsequently inactivate C/EBPα. In fact, compared to normal bone marrow mononuclear cells, c-Jun expression is increased in AML patient samples (Affymetrix expression microarray analysis, n = 166). c-Jun binds to C/EBPα via the leucine zipper domains and prevents C/EBPα from DNA binding. Inactivation of C/EBPα by c-Jun is necessary for c-Jun to induce proliferation because c-Jun-induced proliferation can be prevented by ectopic overexpression of C/EBPα. The dominant-negative 30-kDa C/EBPα protein, found in AML, fails to downregulate c-Jun mRNA expression in AML patient samples. Thus, our data suggest a model for AML in which c-Jun promotes proliferation and prevents differentiation by inhibiting C/EBPα DNA binding via leucine zipper domain interaction. It might depend on the expression levels of C/EBPα and c-Jun, if inhibition of C/EBPα by c-Jun or if inhibition of c-Jun by C/EBPα is more predominant: proliferation versus differentiation; AML versus normal myeloid development.