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.

作为细胞极性的中央调节器，CDC42 GTPase的活性在维持正常的造血干细胞和祖细胞（HSC / P）功能方面受到严格控制。我们发现，HSC / P向急性髓细胞性白血病（AML）的转化与白血病细胞中CDC42表达和活性的增加有关。在AML小鼠模型中，Cdc42的丧失消除了MLL-AF9–导致AML的发展。此外，在小鼠和人类MLL-AF9（MA9）细胞中CDC42的遗传消融降低了存活率并诱导了克隆性白血病引发细胞的分化。我们显示MLL-AF9白血病细胞在升高的Cdc42-鸟苷三磷酸活性的背景下保持细胞极性，类似于非恶性，年轻的HSC / Ps。Cdc42的丢失导致去极化AML细胞的转移，这与对称和不对称细胞分裂的频率降低相关，从而产生能够自我更新的子代细胞。重要的是，我们证明在原代人AML细胞中可诱导的CDC42抑制作用会在异种移植模型中阻止白血病的进展。因此，CDC42丢失会抑制AML细胞的极性和分裂不对称性，