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

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

doi:10.1182/blood-2016-12-758458

Cited by 37 publications

(34 citation statements)

References 40 publications

(79 reference statements)

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“…In the context of FA, a recent study used primary BM samples from FA patients and patient-derived FA lymphoblast cell lines to demonstrate that the human FA hematopoietic cells have an intrinsic decrease in the activity of Cdc42 [25]. Another recent study shows that Cdc42 is a cell polarity determinant and controls cell division symmetry to block leukemia cell differentiation [44]. Our unpublished data indicate that FA murine HPSCs also exhibit lower Cdc42 activity compared with the WT counterparts and that Cdc42 is de-polarized in FA HSCs (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Reduced Cell Division Control Protein 42 Activity Compromises Hematopoiesis-Supportive Function of Fanconi Anemia Mesenchymal Stromal Cells

Cole

et al. 2018

Stem Cells

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Hematopoietic stem cells preserve their ability to self-renew and differentiate to different lineages in the bone marrow (BM) niche, which is composed in large part by BM stromal cells. Studies have shown that altered signaling in the BM niche results in leukemia initiation or progression. Fanconi anemia (FA) is an inherited BM failure syndrome associated with extremely high risk of leukemic transformation. By using two FA mouse models, here we have investigated the hematopoiesis-supportive function of FA BM mesenchymal stroma cells (MSCs). We found that MSCs deficient for Fanca or Fancc gene are defective in proliferation and prone to undergo senescence in vitro. Mechanistically, we show that the activity of cell division control protein 42 (Cdc42), a Rho GTPase known to be a critical regulator for cytoskeleton organization, is significantly reduced in FA MSCs. Furthermore, we demonstrate that this reduction in Cdc42 activity plays a causal role in defective hematopoiesis-supportive function of the FA MSCs. The progenies of wild-type hematopoietic stem and progenitor cells cocultured on FA MSCs exhibit compromised self-renewal capacity both in vitro and in vivo. Genetic correction of FA deficiency restores Cdc42 activity and improves the hematopoiesis-supportive capacity of FA MSC. Finally, ectopic expression of a constitutively active Cdc42 mutant, Cdc42F28L, or pretreatment with Wnt5a, increases the active Cdc42 level and rescues the hematopoietic supportive defects of FA MSCs. Taken together, our results identify a novel link between Cdc42 activity and the hematopoiesis-supportive function of MSCs and suggest that a niche-specific increase of Cdc42 activity may be beneficial for FA therapy. Stem Cells 2018;36:785-795.

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Section: Discussionmentioning

confidence: 99%

Reduced Cell Division Control Protein 42 Activity Compromises Hematopoiesis-Supportive Function of Fanconi Anemia Mesenchymal Stromal Cells

Cole

et al. 2018

Stem Cells

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“…In contrast, only 2.5% (1 out of 40 mice) of cultured single SoNar-low cells from symmetrical cell divisions could initiate leukemia ( Figures S5C-S5E). Mechanistically, some genes key to symmetric (CDC42) (Mizukawa et al, 2017) or nonsymmetric cell divisions (Lis1) (Zimdahl et al, 2014) were analyzed in these cells, which showed that SoNar-high cells expressed 4.5-fold higher level of CDC42, but 2.7-fold lower level of Lis1, than that of SoNar-low cells ( Figure S5F).…”

Section: Sonar-high Aml Cells Have Enhanced Capacities Of Symmetric Dmentioning

confidence: 99%

Metabolic Imaging Reveals a Unique Preference of Symmetric Cell Division and Homing of Leukemia-Initiating Cells in an Endosteal Niche

Hao

Chen

et al. 2019

Cell Metabolism

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Graphical Abstract Highlights d SoNar serves as a unique tool for in vitro/in vivo studies of stem cell metabolisms d SoNar-high cells prefer glycolysis and are enriched for leukemia-initiating cells d Leukemia-initiating cells home to endosteal niches and prefer symmetric divisions d PDK2 sustains metabolic and leukemogenic activities of leukemia-initiating cells In Brief Hao et al. reveal that a genetically encoded metabolic sensor, SoNar, precisely monitors the metabolic status of leukemia-initiating cells (LICs) both in vitro and in vivo. LICs prefer homing to endosteal niches and symmetric divisions to maintain their leukemogenic activities. PDK2 fine-tunes the glycolysis and cell-fate determinations of LICs. Hao et al., 2019, Cell Metabolism 29, 950-965 April 2, 2019 ª 2018 Elsevier Inc. SUMMARYThe metabolic properties of leukemia-initiating cells (LICs) in distinct bone marrow niches and their relationships to cell-fate determinations remain largely unknown. Using a metabolic imaging system with a highly responsive genetically encoded metabolic sensor, SoNar, we reveal that SoNar-high cells are more glycolytic, enriched for higher LIC frequency, and develop leukemia much faster than SoNar-low counterparts in an MLL-AF9-induced murine acute myeloid leukemia model. SoNar-high cells mainly home to and locate in the hypoxic endosteal niche and maintain their activities through efficient symmetric division. SoNar can indicate the dynamics of metabolic changes of LICs in the endosteal niche. SoNar-high human leukemia cells or primary samples have enhanced clonogenic capacities in vitro or leukemogenesis in vivo. PDK2 fine-tunes glycolysis, homing, and symmetric division of LICs. These findings provide a unique angle for the study of metabolisms in stem cells, and may lead to development of novel strategies for cancer treatment.

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“…Cdc42 is a Rho family small GTPase that was first discovered in Saccharomyces cerevisiae (Johnson and Pringle, 1990). It plays a role in cell migration, polarity, differentiation and proliferation, as well as branching of blood vessels and regulation of actin dynamics (Lavina et al, 2018;Melendez et al, 2013;Mizukawa et al, 2017;Nguyen et al, 2017;Schulz et al, 2015). Cdc42 is a molecular switch that cycles between active (GTP-bound) and inactive (GDPbound) states through its interaction with guanine exchange factors (GEFs) and GTPase activating proteins (GAPs) (Bishop and Hall, 2000;Schmidt and Hall, 2002).…”

Section: Introductionmentioning

confidence: 99%

Dynamin binding protein is required forXenopus laeviskidney development

DeLay

Baldwin

Miller

2018

Preprint

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The adult human kidney contains over one million nephrons, with each nephron consisting of a tube containing segments that have specialized functions in nutrient and water absorption and waste excretion. The embryonic kidney of Xenopus laevis consists of a single functional nephron composed of regions that are analogous to those found in the human nephron, making it a simple model for the study of nephrogenesis. The exocyst complex, which traffics proteins to the cell membrane in vesicles via CDC42, is essential for normal kidney development. Here, we show that the CDC42-GEF, dynamin binding protein (Dnmbp/Tuba), is essential for nephrogenesis in Xenopus. dnmbp is expressed in Xenopus embryo kidneys during development, and knockdown of Dnmbp using two separate morpholino antisense oligonucleotides results in reduced expression of late pronephric markers, whereas the expression of early markers of nephrogenesis remains unchanged. A greater reduction in expression of markers of differentiated distal and connecting tubules was seen in comparison to proximal tubule markers, indicating that Dnmbp reduction may have a greater impact on distal and connecting tubule differentiation. dnmbp knockout using CRISPR results in a similar reduction of late markers of pronephric tubulogenesis. Overexpression of dnmbp in the kidney also resulted in disrupted pronephric tubules, suggesting that dnmbp levels in the developing kidney are tightly regulated, with either increased or decreased levels leading to developmental defects. Together, these data suggest that Dnmbp is required for nephrogenesis.

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

Cited by 37 publications

References 40 publications

Reduced Cell Division Control Protein 42 Activity Compromises Hematopoiesis-Supportive Function of Fanconi Anemia Mesenchymal Stromal Cells

Reduced Cell Division Control Protein 42 Activity Compromises Hematopoiesis-Supportive Function of Fanconi Anemia Mesenchymal Stromal Cells

Metabolic Imaging Reveals a Unique Preference of Symmetric Cell Division and Homing of Leukemia-Initiating Cells in an Endosteal Niche

Dynamin binding protein is required forXenopus laeviskidney development

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