ausblenden:
Schlagwörter:
PLURIPOTENT STEM-CELLS; ACUTE MYELOID-LEUKEMIA; MLL-REARRANGED AML;
TRANSCRIPTION FACTORS; SUPER-ENHANCERS; HEMATOPOIETIC DIFFERENTIATION;
SELECTIVE-INHIBITION; SIGNALING PATHWAYS; HIGHLY EFFICIENT;
SOMATIC-CELLS
Zusammenfassung:
Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBP alpha (B alpha' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBP alpha post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBP alpha also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. B alpha' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBP alpha.
