C/EBRγ deregulation results in differentiation arrest in acute myeloid leukemia

C/EBPs are a family of transcription factors that regulate growth. control and differentiation of various tissues. We found that C/EBP gamma is highly upregulated in a subset of acute Myeloid leukemia (AML) samples characterized by C/EBP alpha hypermethylation/silencing Similarly, C/EBP gamma was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBP alpha, as C/EBP alpha mediates C/EBP gamma suppression. Studies in myeloid cells demonstrated that CEBP6 overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation hi addition, treatment of these leukemias with demethylating agents restored the. C/EBP alpha-C/EBP gamma balance and upregulated the expression of myeloid differentiation markers. Our-results indicate that C/EBP gamma mediates the myeloid differentiation arrest induced by C/EBP alpha deficiency and that targeting the C/EBP alpha-C/EBP gamma axis rescues neutrophilic differentiation in this unique subset of AMLs.