Targeting C/EBPalpha p42 and oncogene cooperativity in acute myeloid leukaemia

Lohan, F., O'Connor, C., Campos, J., Ohlsson, E., Salome, M. , Forde, C., Cahill, M., Kiely, P., Porse, B. and Keeshan, K. (2014) Targeting C/EBPalpha p42 and oncogene cooperativity in acute myeloid leukaemia. Experimental Hematology, 42(8), S42. (doi: 10.1016/j.exphem.2014.07.153)

Abstract

C/EBPalpha (42 kDa) is commonly dysregulated in acute myeloid leukaemia (AML) by mutation or via the action of AML oncogenes, which can increase the 30 kDa protein oncogenic form of C/EBPalpha (p30). The Trib2 oncogene is associated with dysregulated C/EBPalpha in human AML and leads to the degradation of p42, leaving p30 intact. Indeed there exists a novel paradigm whereby an E2F1-p30-Trib2 positive regulatory loop and an E2F1-p42-Trib2 negative feedback loop plays a key role in Trib2 expression, essential for AML cell proliferation and survival. Thus, it is important to understand the Trib2-C/EBPalpha relationship in the context of p42 degradation and/or C/EBPalpha mutation in AML. Using mouse genetics our data reveals that in the absence of C/EBPalpha (-/-) Trib2 was unable to induce AML whereas in the presence of p42 and mutant p30 (L/+), Trib2 and p30 cooperate to decrease the latency of AML disease. In the situation where p30 is expressed in the absence of p42, which alone can lead to AML (L/L), Trib2 does not lead to a more aggressive disease than that caused by p30 itself. These data show that the modulation of p42 rather than the expression of p30 is a key driver in Trib2 AML. Peptide array analysis showed the site-specific direct interaction between Trib2 and p42, and mutational analysis showed that these site-specific interactions were required for the K48-specific ubiquitin-dependent proteasomal degradation of p42. A C-terminal lysine residue of C/EBPalpha commonly found duplicated in AML patients was critical for Trib2-mediated p42 ubiquitination and proteasomal degradation. Proteasome inhibition using bortezomib induced cell death in Trib2 positive AML cell lines and AML patient samples in vitro and in vivo. Knockdown and overexpression of Trib2 in AML cells followed by transplantation in NSG mice and treated with bortezomib selectively killed Trib2 positive AML. Our data show the mechanism required for oncogene function centres on p42 degradation.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Keeshan, Dr Karen and Salome, Ms Mara and Campos, Ms Joana and O'Connor, Ms Caitriona
• Authors: Lohan, F., O'Connor, C., Campos, J., Ohlsson, E., Salome, M., Forde, C., Cahill, M., Kiely, P., Porse, B., and Keeshan, K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Experimental Hematology
• Publisher: Elsevier
• ISSN: 0301-472X