The Cell Polarity Determinant CDC42 Controls Division Symmetry to Block Leukemia Cell Differentiation

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2017 Aug 6

PMID 28778865

Citations 25

Authors

Benjamin Mizukawa

Eric OBrien

Daniel C Moreira

Mark Wunderlich

Cindy L Hochstetler

Xin Duan

Wei Liu

Emily Orr

H Leighton Grimes

James C Mulloy

Yi Zheng

Affiliations

Soon will be listed here.

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 -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.

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