Abstract
In acute myeloid leukemia (AML), the transcription factors CEBPA and KLF4 as well as the universal tumor suppressor p53 are frequently deregulated. Here, we investigated the extent of dysregulation, the molecular interactions, and the mechanisms involved. One hundred ten AML patient samples were analyzed for protein levels of CEBPA, KLF4, p53, and p53 modulators. Regulation of CEBPA gene expression by KLF4 and p53 or by chemical p53 activators was characterized in AML cell lines. We found that CEBPA gene transcription can be directly activated by p53 and KLF4, suggesting a p53-KLF4-CEBPA axis. In AML patient cells, we observed a prominent loss of p53 function and concomitant reduction of KLF4 and CEBPA protein levels. Assessment of cellular p53 modulator proteins indicated that p53 inactivation in leukemic cells correlated with elevated levels of the nuclear export protein XPO1/CRM1 and increase of the p53 inhibitors MDM2 and CUL9/PARC in the cytoplasm. Finally, restoring p53 function following treatment with cytotoxic chemotherapy compounds and p53 restoring non-genotoxic agents induced CEBPA gene expression, myeloid differentiation, and cell-cycle arrest in AML cells. The p53-KLF4-CEBPA axis is deregulated in AML but can be functionally restored by conventional chemotherapy and novel p53 activating treatments.
Highlights
CCAAT/enhancer-binding protein alpha (CEBPA) is a lineagespecific transcription factor expressed in hematopoietic stem and myeloid progenitor cells [1]
We found that CEBPA gene transcription can be directly activated by p53 and KLF4, suggesting a p53–KLF4– CEBPA axis
The p53–KLF4–CEBPA axis is deregulated in acute myeloid leukemia (AML) but can be functionally restored by conventional chemotherapy and novel p53 activating treatments
Summary
CCAAT/enhancer-binding protein alpha (CEBPA) is a lineagespecific transcription factor expressed in hematopoietic stem and myeloid progenitor cells [1]. CEBPA functions as a differentiation factor by directly targeting lineage-specific genes. CEBPA activates granulocyte- and eosinophil-specific genes while inhibiting erythroid- and lymphoid-specific factors. CEBPA acts as a potent cell-cycle inhibitor. The mechanisms by which CEBPA mediates cell-cycle arrest have been extensively investigated, and they involve the ability of CEBPA to upregulate the CDKN1A gene encoding the cyclin-dependent kinase inhibitor p21/WAF1/Cip, its interaction with the cyclin-dependent kinases CDK2 and CDK4, and the CEBPA-mediated repression of the E2F complex [2]. CEBPA function is commonly deregulated in patients with AML due to genomic mutations, suppressed transcriptional
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