C/EBPalpha and the pathophysiology of acute myeloid leukemia.
OBJECTIVE
The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder.


RESULTS
Conditional mouse models provide direct evidence that loss of C/EBPalpha function leads to the accumulation of myeloid blasts in the bone marrow. Targeted disruption of the wild type C/EBPalpha protein, while conserving the dominant-negative 30 kDa isoform of C/EBPalpha, induces an AML-like disease in mice. In hematopoietic stem cells C/EBPalpha serves to limit cell self-renewal. Finally, C/EBPalpha function is disrupted at different levels in specific subgroups of acute myeloid leukemia patients.


CONCLUSIONS
There is evidence that impaired C/EBPalpha function contributes directly to the development of acute myeloid leukemia. Normal myeloid development and acute myeloid leukemia are now thought to reflect opposite sides of the same hematopoietic coin. Restoring C/EBPalpha function represents a promising target for novel therapeutic strategies in acute myeloid leukemia.
Mueller
Beatrice U
BU
Department of Internal Medicine, University Hospital, Switzerland.
Pabst
Thomas
T
D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D038042:Myelopoiesis
D022763:CCAAT-Enhancer-Binding Protein-alpha