Inactivation of the p53-KLF4-CEBPA Axis in Acute Myeloid Leukemia.

Seipel, Katja; Marques, Miguel Teixera; Bozzini, Marie-Ange; Meinken, Christina; Mueller, Beatrice U; Pabst, Thomas (2016). Inactivation of the p53-KLF4-CEBPA Axis in Acute Myeloid Leukemia. Clinical cancer research, 22(3), pp. 746-756. American Association for Cancer Research 10.1158/1078-0432.CCR-15-1054

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PURPOSE 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. EXPERIMENTAL DESIGN 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. RESULTS 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. CONCLUSIONS The p53-KLF4-CEBPA axis is deregulated in AML but can be functionally restored by conventional chemotherapy and novel p53 activating treatments. Clin Cancer Res; 22(3); 746-56. ©2015 AACR.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)

UniBE Contributor:

Seipel, Katja and Pabst, Thomas

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1078-0432

Publisher:

American Association for Cancer Research

Language:

English

Submitter:

Marianne Zahn

Date Deposited:

05 Apr 2016 13:24

Last Modified:

11 Jul 2018 17:16

Publisher DOI:

10.1158/1078-0432.CCR-15-1054

PubMed ID:

26408402

BORIS DOI:

10.7892/boris.77192

URI:

https://boris.unibe.ch/id/eprint/77192

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