SIRT2 regulates proliferation and chemotherapy response of MLL-ENL-driven acute myeloid leukemia.

Both MLL-AF9 and MLL-ENL leukemia fusion proteins drive oncogenic transformation of hematopoietic cells through their N-terminal DNA/histone binding mixed-lineage leukemia 1 domain and C-terminal fragment of AF9 or ENL containing an unstructured linker region and the ANC1 homology domain, which recruits transcription factors. Despite of their structural similarity, acute myeloid leukemia (AML) patients bearing MLL-ENL show more adverse outcomes compared to those with MLL-AF9. We recapitulated the clinical patterns of these two MLL-fusions driven AMLs using murine models and found that MLL-ENL AML cells showed slower cell cycle progression and more resistance to standard chemotherapy than MLL-AF9 cells. These phenotypes were primarily controlled by the linker regions of ENL and a highly conserved lysine residue K469 within. Substitution of K469 with an acetylated mimic glutamine abolished the ability of MLL-ENL to suppress proliferation and promote chemo-resistance. We showed that deacetylase Sirt2 might act as an upstream regulator of MLL-ENL. Deletion of Sirt2 promoted proliferation of AML cells with either MLL fusions. Importantly, loss of Sirt2 greatly enhanced the sensitivity of the MLL-ENL AML cells to chemo-treatment. Taken together, our study uncovered a unique regulatory role of Sirt2 in leukemogenesis and suggested targeting SIRT2 as a new way to sensitize MLL-ENL AML patience for chemotherapy.

Myc-Miz1 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 (AMLs). 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 transactivational and Myc-interacting zinc finger protein 1 (Miz1)-mediated transrepressional activities. The role of Myc-Max-mediated transactivation in the pathogenesis of AML has been well studied; however, the role of Myc-Miz1-mediated transrepression in AML is still somewhat obscure. Myc protein harboring a V394D mutation (MycV394D) is a mutant form of Myc that lacks transrepressional activity due to a defect in its ability to interact with Miz1. We found that, compared with Myc, the oncogenic function of MycV394D is significantly impaired. The AML/myeloproliferative disorder that develops in mice receiving MycV394D-transduced hematopoietic stem/progenitor cells (HSPCs) is significantly delayed compared with 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 Myc represses Miz1-mediated expression of CCAAT/enhancer-binding protein α (Cebpα) and Cebpδ, thus playing an important role in the pathogenesis of AML by maintaining the undifferentiated state and self-renewal capacity of LSCs.