The presence of C/EBP[alpha] and its degradation are both required for TRIB2-mediated leukaemia

C/EBP[alpha] (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBP[alpha] p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive. Using mouse genetics, our data reveal that in the complete absence of C/EBP[alpha], TRIB2 was unable to induce AML. Only in the presence of C/EBP[alpha] p42 and p30, were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate that the molecular mechanism involved in the degradation of C/EBP[alpha] p42 requires site-specific direct interaction between TRIB2 and C/EBP[alpha] p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBP[alpha] p42. This interaction and ubiquitination is dependent on a critical C terminal lysine residue on C/EBP[alpha]. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2-positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML, and the direct interaction and degradation of C/EBP[alpha] p42 is required for TRIB2-mediated AML. Oncogene (2016) 35, 5272-5281; doi: 10.1038/onc.2016.66; published online 21 March 2016