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Cell polarity determinant CDC42 controls division symmetry to block leukemia cell differentiation

Benjamin Mizukawa, Eric O'Brien, Daniel C. Moreira, Mark Wunderlich, Cindy L. Hochstetler, Xin Duan, Wei Liu, Emily Orr, H. Leighton Grimes, James C. Mulloy and Yi Zheng

Key points

  • CDC42 regulates AML cell polarity and division symmetry.

  • CDC42 suppression in AML cells promotes differentiation and blocks leukemia progression.

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, 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-GTP activity, similar to previously defined young HSC/P situation. Loss of Cdc42 resulted in a shift to depolarized AML cells that is associated with a decrease in frequency of symmetric and asymmetric cell divisions producing daughter cells capable of self-renewal. Importantly, we demonstrate that inducible CDC42 suppression in primary human patient 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.

  • Submitted December 20, 2016.
  • Accepted July 24, 2017.