The cell polarity determinant CDC42 controls division symmetry to block leukemia cell differentiation
The cell polarity determinant CDC42 controls division symmetry to block leukemia cell differentiation
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DOI：
10.1182/blood-2016-12-758458
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发表时间：
2017-09-14
期刊：
影响因子：
20.3
通讯作者：
Zheng, Yi
中科院分区：
文献类型：
--
作者：
Mizukawa, Benjamin;O'Brien, Eric;Zheng, Yi
作为细胞极性的中心调节剂，CDC 42 GTdR的活性在维持正常造血干细胞和祖细胞（HSC/P）功能中受到严格控制。我们发现HSC/P向急性髓性白血病（AML）的转化与白血病细胞中CDC 42表达和活性增加相关。在AML的小鼠模型中，Cdc 42的丧失消除了MLL-AF 9诱导的AML发展。此外，在鼠和人MLL-AF 9（MA 9）细胞中的CDC 42的基因消融降低了克隆性白血病起始细胞的存活率和诱导分化。我们发现MLL-AF 9白血病细胞在Cdc 42-三磷酸鸟苷活性升高的情况下保持细胞极性，类似于非恶性的年轻HSC/Ps。Cdc 42的丢失导致向去极化AML细胞的转变，这与产生能够自我更新的子细胞的对称和不对称细胞分裂的频率降低有关。重要的是，我们证明了原代人AML细胞中的诱导型CDC 42抑制阻断了异种移植模型中的白血病进展。因此，CDC 42损失抑制AML细胞极性和分裂不对称性，并且CDC 42构成改变白血病起始细胞命运用于分化治疗的有用靶标。
As a central regulator of cell polarity, the activity of CDC42 GTPase is tightly controlled in maintaining normal hematopoietic stem and progenitor cell (HSC/P) functions. We found that transformation of HSC/P to acute myeloid leukemia (AML) is associated with increased CDC42 expression and activity in leukemia cells. In a mouse model of AML, the loss of Cdc42 abrogates MLL-AF9-induced AML development. Furthermore, genetic ablation of CDC42 in both murine and human MLL-AF9 (MA9) cells decreased survival and induced differentiation of the clonogenic leukemia-initiating cells. We show that MLL-AF9 leukemia cells maintain cell polarity in the context of elevated Cdc42-guanosine triphosphate activity, similar to nonmalignant, young HSC/Ps. The loss of Cdc42 resulted in a shift to depolarized AML cells that is associated with a decrease in the frequency of symmetric and asymmetric cell divisions producing daughter cells capable of self-renewal. Importantly, we demonstrate that inducible CDC42 suppression in primary human AML cells blocks leukemia progression in a xenograft model. Thus, CDC42 loss suppresses AML cell polarity and division asymmetry, and CDC42 constitutes a useful target to alter leukemia-initiating cell fate for differentiation therapy.