A C/ebpα isoform-specific differentiation program in primary myelocytes
Garcia-Cuellar, M.-P.; Akan, S.; Slany, R. K.
Show abstract
The transcription factor CCAAT-enhancer binding factor alpha (C/ebp) is a master controller of myeloid differentiation that is expressed as long (p42) and short (p30) isoform. Mutations within the CEBPA gene selectively deleting p42 are frequent in human acute myeloid leukemia. Here we investigated the individual genomics and transcriptomics of p42 and p30. Both proteins bound to identical sites across the genome. For most targets, they induced a highly similar transcriptional response with the exception of a few isoform-specific genes. Amongst those we identified early growth response 1 (Egr1) and tribbles 1 (Trib1) as key targets selectively induced by p42 that are also underrepresented in CEBPA-mutated AML. Egr1 executed a program of myeloid differentiation and growth arrest. Oppositely, Trib1 established a negative feedback loop through activation of Erk1/2 kinase thus placing differentiation under control of signaling. Unexpectedly, differentiation elicited either by removal of an oncogenic input or by G-CSF did not peruse C/ebp as mediator but rather directly affected the cell cycle core by upregulation of p21/p27 inhibitors. This points to functions downstream of C/ebp as intersection point where transforming and differentiation stimuli converge and this finding offers a new perspective for therapeutic intervention.
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