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The cell polarity determinant CDC42 controls division symmetry to block leukemia cell differentiation.


ABSTRACT: 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.

SUBMITTER: Mizukawa B 

PROVIDER: S-EPMC5600140 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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The cell polarity determinant CDC42 controls division symmetry to block leukemia cell differentiation.

Mizukawa Benjamin B   O'Brien Eric E   Moreira Daniel C DC   Wunderlich Mark M   Hochstetler Cindy L CL   Duan Xin X   Liu Wei W   Orr Emily E   Grimes H Leighton HL   Mulloy James C JC   Zheng Yi Y  

Blood 20170804 11


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 <i>MLL-AF9</i>-induced AML development. Furthermore, genetic ablation of CDC42 in both murine and human MLL-AF9 (MA9) cells dec  ...[more]

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