Superenhancing Aml With Trib1

In this issue of Blood, Yoshino et al use the genetic Trib1-ROSA26-Cre-knockout murine model and retroviral-mediated HoxA9 overexpression, together or not with Trib1 reexpression (Trib1 Hi and Trib1 null), to investigate the mechanistic basis for HoxA9-mediated acutemyeloid leukemia (AML).(1) They have deciphered the mechanism involved in HoxA9-associated AML, linking an Erg-specific superenhancer with the Trib1-C/EBP alpha axis. It has previously been shown that TRIB proteins, including TRIB1 and TRIB2, are AML oncoproteins capable of driving disease development. Degradation of the p42 isoform of C/EBP alpha (an important myeloid transcription factor) and increased MAPK/ERK signaling (a proliferation and survival indicator) are key molecular mechanisms for Trib oncogenic activity.(2) Cooperation with HoxA9 leads to accelerated AML development,(3,4) which is important because HoxA9 overexpression alone is unable to drive AML in vivo. The role that TRIB proteins may have across the wide heterogeneity of AML phenotypes is still underappreciated; however, given that deregulated Hox signaling is associated with similar to 70% of all AMLs, it is important to understand the involvement of Trib oncogenic activities in HoxA9-mediated AML. It remained an open question how TRIB proteins cooperate with Hoxa9 at the mechanistic level.