Myc-Miz-1 signaling promotes self-renewal of leukemia stem cells by repressing Cebpα and Cebpδ.
c-Myc (Myc hereafter) is found to be deregulated and/or amplified in most acute myeloid leukemias (AML). Almost all AML cells are dependent upon Myc for their proliferation and survival. Thus Myc has been proposed as a critical anti-AML target. Myc has Max-mediated trans-activational and Miz1-mediated trans-repressional activities. The role of Myc-Max-mediated trans-activation in the pathogenesis of AML has been well-studied; however the role of Myc-Miz1-mediated trans-repression in AML is still somewhat obscure. MycV394D is a mutant form of Myc which lacks trans-repressional activity due to a defect in its ability to interact with Miz1. We found that, compared to Myc, the oncogenic function of MycV394D is significantly impaired. The AML/myeloproliferative disorder which develops in mice receiving MycV394D-transduced hematopoietic stem/progenitor cells (HSPCs) is significantly delayed compared to mice receiving Myc-transduced HSPCs. Using a murine MLL-AF9 AML model, we found that AML cells expressing MycV394D (intrinsic Myc deleted) are partially differentiated and show reductions in both colony-forming ability in vitro and leukemogenic capacity in vivo. The reduced frequency of leukemia stem cells (LSCs) among MycV394D-AML cells and their reduced leukemogenic capacity during serial transplantation suggest that Myc-Miz1 interaction is required for the self-renewal of LSCs. In addition, we found that MycV394D-AML cells are more sensitive to chemotherapy than are Myc-AML cells. Mechanistically, we found that the Myc represses Miz1-mediated expression of Cebpα and Cebpδ, thus playing an important role in the pathogenesis of AML by maintaining the undifferentiated state and self-renewal capacity of LSCs.