Loss of FBXO9 Enhances Proteasome Activity and Promotes Aggressiveness in Acute Myeloid Leukemia
Loss of FBXO9 Enhances Proteasome Activity and Promotes Aggressiveness in Acute Myeloid Leukemia
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DOI：
10.3390/cancers11111717
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发表时间：
2019-11-01
期刊：
影响因子：
5.2
通讯作者：
Buckley, Shannon M.
中科院分区：
文献类型：
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作者：
Hynes-Smith, R. Willow;Swenson, Samantha A.;Buckley, Shannon M.
造血系统在整个生命过程中由能够分化成所有造血谱系的干细胞维持。维持造血需要自我更新、分化和静止之间的密切平衡，这种平衡的破坏可能导致恶性转化。与健康骨髓相比，来自SCF E3泛素连接酶家族的底物识别组分FBXO 9在急性髓性白血病（AML）患者中下调，并且这种下调在inv（16）AML患者中尤其明显。为了研究FBXO 9在恶性造血中的作用，我们使用新的CRISPR/Cas9策略产生了条件性敲除小鼠模型。Fbxo 9在鼠造血系统中的缺失显示对干细胞和祖细胞功能没有不利影响，但在AML中导致inv小鼠中显著加速和侵袭性白血病发展（16）。Fbxo 9不仅在白血病发生中发挥作用，而且还能维持AML活性并促进疾病进展。原发性肿瘤的定量质谱分析揭示缺乏Fbxo 9的肿瘤高度表达与转移和侵袭相关的蛋白以及泛素蛋白酶体系统的组分。我们证实FBXO 9的缺失导致蛋白酶体活性增加，并且肿瘤细胞对硼替佐米的体外蛋白酶体抑制更敏感，这表明FBXO 9表达可以预测患者对硼替佐米的反应。
The hematopoietic system is maintained throughout life by stem cells that are capable of differentiating into all hematopoietic lineages. An intimate balance between self-renewal, differentiation, and quiescence is required to maintain hematopoiesis and disruption of this balance can result in malignant transformation. FBXO9, the substrate recognition component from the SCF E3 ubiquitin ligase family, is downregulated in patients with acute myeloid leukemia (AML) compared to healthy bone marrow, and this downregulation is particularly evident in patients with inv(16) AML. To study FBXO9 in malignant hematopoiesis, we generated a conditional knockout mouse model using a novel CRISPR/Cas9 strategy. Deletion of Fbxo9 in the murine hematopoietic system showed no adverse effects on stem and progenitor cell function but in AML lead to markedly accelerated and aggressive leukemia development in mice with inv(16). Not only did Fbxo9 play a role in leukemia initiation but it also functioned to maintain AML activity and promote disease progression. Quantitative mass spectrometry from primary tumors reveals tumors lacking Fbxo9 highly express proteins associated with metastasis and invasion as well as components of the ubiquitin proteasome system. We confirmed that the loss of FBXO9 leads to increased proteasome activity and tumors cells were more sensitive to in vitro proteasome inhibition with bortezomib, suggesting that FBXO9 expression may predict patients' response to bortezomib.