Reintroduction of C/EBPalpha in leukemic CD34+ stem/progenitor cells impairs self-renewal and partially restores myelopoiesis.

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Schepers H, Wierenga AT, van Gosliga D, Eggen BJ, Vellenga E, Schuringa JJ

Reintroduction of C/EBPalpha in leukemic CD34+ stem/progenitor cells impairs self-renewal and partially restores myelopoiesis.

Blood. 2007 Aug 15;110(4):1317-25. Epub 2007 May 2.

PubMed ID

17475913 [ View in PubMed

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Abstract

The CCAAT/enhancer binding protein (C/EBP) alpha transcription factor is indispensable for myeloid differentiation. In various myeloid leukemias, C/EBPalpha is mutated or functionally impaired due to decreased C/EBPalpha expression or phosphorylation. In order to investigate the functional consequences of decreased C/EBPalpha function in AML, we reintroduced C/EBPalpha in primary CD34(+) sorted acute myeloid leukemia (AML) cells using a lentiviral approach. Self-renewal and differentiation of primary AML stem cells were studied on long-term MS5 cocultures. Activation of C/EBPalpha immediately led to a growth arrest in all AML cultures (N = 7), resulting in severely reduced expansion compared with control cultures. This growth arrest corresponded with enhanced myeloid differentiation as assessed by fluorescence-activated cell sorter (FACS) analysis for CD14, CD15, and CD11b. Myeloid differentiation was further confirmed by the up-regulation of neutrophil elastase and granulocyte colony-stimulating factor (G-CSF) receptor in C/EBPalpha transduced cells. C/EBPalpha-expressing AML CD34(+) cells failed to generate second and third leukemic cobblestone areas (L-CAs) in serial replating experiments, while control cultures could be sequentially passaged for more than 4 times, indicating that reintroduction of C/EBPalpha impaired the self-renewal capacity of the leukemic CD34(+) compartment. Together, our data indicate that low C/EBPalpha levels are necessary to maintain self-renewal and the immature character of AML stem cells.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Pegfilgrastim	Neutrophil elastase	Protein	Humans	No	Substrate	Details