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

Abstract

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