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.

中文翻译：

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Myc-Miz-1 信号通过抑制 CebpU+03B1 和 CebpU+03B4 促进白血病干细胞的自我更新

c-Myc（以下简称 Myc）被发现在大多数急性髓性白血病 (AML) 中失调和/或扩增。几乎所有 AML 细胞的增殖和存活都依赖于 Myc。因此，Myc 已被提议作为关键的反 AML 目标。Myc 具有 Max 介导的反式激活和 Miz1 介导的反式抑制活动。Myc-Max 介导的反式激活在 AML 发病机制中的作用已得到充分研究；然而，Myc-Miz1 介导的反式抑制在 AML 中的作用仍然有些模糊。MycV394D 是 Myc 的突变形式，由于其与 Miz1 相互作用的能力存在缺陷，因此缺乏反式抑制活性。我们发现，与 Myc 相比，MycV394D 的致癌功能明显受损。与接受 Myc 转导的 HSPC 的小鼠相比，在接受 MycV394D 转导的造血干细胞/祖细胞 (HSPC) 的小鼠中发生的 AML/骨髓增生性疾病显着延迟。使用小鼠 MLL-AF9 AML 模型，我们发现表达 MycV394D（固有 Myc 缺失）的 AML 细胞部分分化，并显示体外集落形成能力和体内白血病生成能力均降低。MycV394D-AML 细胞中白血病干细胞 (LSC) 的频率降低及其在连续移植过程中白血病发生能力的降低表明 Myc-Miz1 相互作用是 LSC 自我更新所必需的。此外，我们发现 MycV394D-AML 细胞比 Myc-AML 细胞对化疗更敏感。从机制上讲，我们发现 Myc 抑制 Miz1 介导的 Cebpα 和 Cebpδ 表达，