The Role of Inhibition of Apoptosis by C/EBPalpha and C/EBPalpha oncoproteins in AML.

AML is the 3rd leading cause of cancer related death in children. Despite treatment intensification, only approximately half of children survive their disease.

Our studies indicate that C/EBP and its AML mutants interact directly with NF-B p50 through the basic region. Through binding to a DNA B site they activate several antiapoptotic genes including BCL2 and FLIP, thereby inhibiting both the extrinsic  and intrinsic apoptotic pathways. These effects are retained by the AML mutants and do not depend on DNA binding but rather on the integrity of the basic region, explaining its conservation in C/EBP AMLs. Interaction with p50 is necessary for the induction of bcl-2 and FLIP but not of myeloid differentiation genes such as neutrophil elastase. The antiapoptotic effect of C/EBPis reproduced by C/EBP. Until now C/EBPwas considered a tumor suppressor, its loss blocking differentiation.

Our data suggest that C/EBP and its AML mutants actively block apoptosis providing a survival advantage to the leukemic blast and that C/EBP acts similarly in lymphoma. These results underscore the importance of the C/EBP:NF-B p50 complex and provide the basis for the proposed experiments and for our long term goal to interrupt this interaction as a therapeutic target.