Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada.
Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada.
Leukemia. 2019 Jan;33(1):110-121. doi: 10.1038/s41375-018-0166-1. Epub 2018 Jun 20.
Growth factor independent 1 (Gfi1) controls myeloid differentiation by regulating gene expression and limits the activation of p53 by facilitating its de-methylation at Lysine 372. In human myeloid leukemia, low GFI1 levels correlate with an inferior prognosis. Here, we show that knockdown (KD) of Gfi1 in mice causes a fatal myeloproliferative disease (MPN) that could progress to leukemia after additional mutations. Both KO and KD mice accumulate myeloid cells that show signs of metabolic stress and high levels of reactive oxygen species. However, only KO cells have elevated levels of Lysine 372 methylated p53. This suggests that in contrast to absence of GFI1, KD of GFI1 leads to the accumulation of myeloid cells because sufficient amount of GFI1 is present to impede p53-mediated cell death, leading to a fatal MPN. The combination of myeloid accumulation and the ability to counteract p53 activity under metabolic stress could explain the role of reduced GF1 expression in human myeloid leukemia.
生长因子独立 1（Gfi1）通过调节基因表达来控制髓系分化，并通过促进赖氨酸 372 的去甲基化来限制 p53 的激活。在人类髓系白血病中，低水平的 GFI1 与预后不良相关。在这里，我们表明，在小鼠中敲低（KD）Gfi1 会导致致命的骨髓增生性疾病（MPN），在额外突变后可能进展为白血病。KO 和 KD 小鼠均积累表现出代谢应激和高水平活性氧特征的髓系细胞。然而，只有 KO 细胞中 Lysine 372 甲基化的 p53 水平升高。这表明，与 GFI1 缺失相反，KD GFI1 导致髓系细胞的积累，因为存在足够量的 GFI1 来阻止 p53 介导的细胞死亡，导致致命的 MPN。髓系细胞积累和在代谢应激下抵消 p53 活性的能力可以解释人类髓系白血病中 GF1 表达减少的作用。
