Over half of all patients with acute myeloid leukemia (AML) succumb to refractory or relapsed disease due to a failure to eradicate the leukemia initiating cells (LICs) at the root of leukemia emergence and propagation. LICs are characterized by acquired capacity for self-renewal and dormancy contributing to chemotherapy resistance. These attributes are conferred by both intrinsic, oncogene-driven factors, as well as signals from interactions with extracellular matrix and soluble factors within a supportive niche in the bone marrow (BM). Preventing the undesired self-renewal potential and promoting a differentiation program in LICs will have therapeutic benefits; however, our rudimentary understanding of the mechanism controlling LIC residency in the niche and its self-renewal regulation limits translation of such a concept to the clinic. A lesson from the regulatory mechanism of hematopoietic stem cells (HSCs) provides useful clues: one model suggests that the type of stem cell division (symmetric vs. asymmetric) determines the cell fate of the resulting daughter cells, with symmetric division resulting in daughter cells with similar regenerative potential and asymmetric division leading to daughter cells with dissimilar fates. Based on our extensive preliminary data and the literature, we propose a novel hypothesis that LIC polarity regulated by intracellular Cdc42 activity affects the LIC cell division symmetry and consequently the self-renewal/differentiation potential. By using an array of highly innovative and multi-disciplinary approaches combining the strength and expertise of the co-principal investigators, we will determine the relationship of Cdc42 regulated cell polarity and division symmetry in LIC self-renewal and differentiation. A potentially causal role of Cdc42 activity in coordinating LIC polarity, division symmetry and differentiation will be established. We will further delineate the Cdc42-mediated signaling pathways that regulate LIC polarity and mode of division, and begin a preclinical testing of the novel strategy of targeting Cdc42 in human AML as a differentiation therapy in mouse xenograft models. The studies will use state of the art animal models, imaging, chemical biology, mouse genetics, and stem cell methodologies like single cell transplants combined with patient derived leukemia samples to define the molecular basis of cell polarity and divisional symmetry and their causal role in determining LIC cell fate.

Public Health Relevance

To maintain active homeostasis, leukemia stem cells (LICs), like normal hematopoietic stem cells, may undergo an asymmetric cell division whereby they segregate cell fate determinants into different daughter cells, maintaining their self-renewal potential. Our work will provide mechanistic insights into LIC cell polarity, division symmetry and cell fate, and establish a proof of principle that targeting cell polarity regulators may promote cancer stem cell differentiation, leading to improve efficacy of conventional chemotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Klauzinska, Malgorzata
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Cincinnati Children's Hospital Medical Center
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Guo, Fukun; Zheng, Yi (2017) Vav1: Friend and Foe of Cancer. Trends Cell Biol 27:879-880
Mizukawa, Benjamin; O'Brien, Eric; Moreira, Daniel C et al. (2017) The cell polarity determinant CDC42 controls division symmetry to block leukemia cell differentiation. Blood 130:1336-1346