Loss of miR-31-5p drives hematopoietic stem cell malignant transformation and restoration eliminates leukemia stem cells in mice
Loss of miR-31-5p drives hematopoietic stem cell malignant transformation and restoration eliminates leukemia stem cells in mice
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miR-31-5p的丢失导致造血干细胞恶化，其恢复可消除白血病干细胞
DOI：
10.1126/scitranslmed.abh2548
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发表时间：
2022-01-26
影响因子：
17.1
通讯作者：
Yan, Daoguang
中科院分区：
文献类型：
--
作者：
Zhu, Biying;Zhong, Wenbin;Yan, Daoguang
白血病干细胞（LSC）传播白血病，并导致治疗患者的高复发率。靶向LSC的能力仍然难以捉摸，这表明需要了解LSC形成的潜在机制。在这里，我们报告了与造血干祖细胞（HSPC）相比，miR-31- 5 p在人类LSC中减少或检测不到。HSPC中miR-31- 5 p的抑制促进其靶基因FIH（编码FIH [抑制缺氧诱导因子Ia（HIF-1 α）的因子]）的表达，以抑制HIF-1 α信号传导。FIH增加导致糖酵解转变为氧化磷酸化（OXPHOS）作为能量代谢的主要模式，并增加了肿瘤代谢产物富马酸的丰度。富马酸盐的增加促进了HSPC向LSC的转化，并在NOD-Prkdc（scid）IL 2 rg（tm 1）/Bcgen（B-NDG）小鼠中引发了髓性白血病样疾病。我们进一步证明了miR-31- 5 p抑制长期和短期造血干细胞，并具有高频率的LSC。与化疗剂Ara-C（阿糖胞苷）组合，使用封装miR-31 - 5 p的G7聚（酰胺胺）纳米级树枝状复合物恢复miR-31 - 5 p消除了LSC并抑制了患者来源的异种移植小鼠模型中的急性髓性白血病（AML）进展。这些结果证明了通过改变能量代谢的HSC恶性转化的机制，并提供了治疗AML患者的潜在治疗策略。
Leukemia stem cells (LSCs) propagate leukemia and are responsible for the high frequency of relapse of treated patients. The ability to target LSCs remains elusive, indicating a need to understand the underlying mechanism of LSC formation. Here, we report that miR-31-5p is reduced or undetectable in human LSCs compared to hematopoietic stem progenitor cells (HSPCs). Inhibition of miR-31-5p in HSPCs promotes the expression of its target gene FIH, encoding FIH [factor inhibiting hypoxia-inducing factor la (HIF-1 alpha)], to suppress HIF-1 alpha signaling. Increased FIH resulted in a switch from glycolysis to oxidative phosphorylation (OXPHOS) as the predominant mode of energy metabolism and increased the abundance of the oncometabolite fumarate. Increased fumarate promoted the conversion of HSPCs to LSCs and initiated myeloid leukemia-like disease in NOD-Prkdc(scid) IL2rg(tm1)/Bcgen (B-NDG) mice. We further demonstrated that miR-31-5p inhibited long- and short-term hematopoietic stem cells with a high frequency of LSCs. In combination with the chemotherapeutic agent Ara-C (cytosine arabinoside), restoration of miR-31-5p using G7 poly (amidoamine) nanosized dendriplex encapsulating miR-31-5p eliminated LSCs and inhibited acute myeloid leukemia (AML) progression in patient-derived xenograft mouse models. These results demonstrated a mechanism of HSC malignant transformation through altered energy metabolism and provided a potential therapeutic strategy to treat patients with AML.