Fanconi anemia type C–deficient hematopoietic stem/progenitor cells exhibit aberrant cell cycle control

Li, Xiaxin; Plett, P. Artur; Yang, Yanzhu; Hong, Ping; Freie, Brian; Srour, Edward F.; Orschell, Christie M.; Clapp, D. Wade; Haneline, Laura S.

doi:10.1182/blood-2003-02-0536

Cited by 30 publications

(26 citation statements)

References 24 publications

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“…In addition, overproduction of Dkk1 induces cell cycling of primitive hematopoietic cells that generally are maintained in a quiescent state (17,28). FA-deficient primitive hematopoietic cells were shown to have an accelerated cell cycle (29). Taken together, these findings support our model and provide a clue to explaining the failure of bone marrow in patients with FA.…”

Section: Discussionsupporting

confidence: 77%

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

Huard

Tremblay

Magron

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Fanconi anemia (FA) is an inherited bone marrow failure syndrome associated with a progressive decline in hematopoietic stem cells, developmental defects, and predisposition to cancer. These various phenotypic features imply a role of FA proteins in molecular events regulating cellular homeostasis. Interestingly, we previously found that the Fanconi C protein (FANCC) interacts with the C-terminalbinding protein-1 (CtBP1) involved in transcriptional regulation. Here we report that FANCC with CtBP1 forms a complex with β-catenin, and that β-catenin activation through glycogen synthase kinase 3β inhibition leads to FANCC nuclear accumulation and FA pathway activation, as measured by the Fanconi D2 protein (FANCD2) monoubiquitination. β-catenin and FANCC nuclear entry is defective in FA mutant cells and in cells depleted of the Fanconi A protein or FANCD2, suggesting that integrity of the FA pathway is required for FANCC nuclear activity. We also report that FANCC with CtBP1 acts as a negative regulator of Dickkopf-1 (DKK1) expression, and that a FA disease-causing mutation in FANCC abrogates this function. Our findings reveal that a defective FA pathway leads to up-regulation of DKK1, a molecule involved in hematopoietic malignancies.

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Section: Discussionsupporting

confidence: 77%

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

Huard

Tremblay

Magron

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…48,49,[56][57][58][59][60][61] We found in multiple experiments that FANCGdeficient MSPCs have decreased clonogenic growth, as well as a decrease in proliferation and survival in vitro. Further, in murine in vitro systems, the microenvironment of FANCG-deficient cells support hematopoiesis less well than unaffected microenvironmental cells with the use of the same pool of hematopoietic cells.…”

Section: Discussionmentioning

confidence: 98%

Mesenchymal stem/progenitor cells promote the reconstitution of exogenous hematopoietic stem cells in Fancg−/− mice in vivo

Chen

Yuan

et al. 2009

Blood

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IntroductionThe microenvironment represents a defined anatomical compartment that provides regulatory signals to hematopoietic stem/ progenitor cells (HSPCs) via interactions with the microenvironment as a 3-dimensional matrix of cells, extracellular matrix molecules, and cell-bound or soluble cytokines and chemokines. [1][2][3][4][5][6] The essential cellular component of this microenvironment, also termed as the "niche," is derived from a common progenitor of mesenchymal origin 7 that gives rise to osteoblasts, self-renewing osteoprogenitors, 3,[8][9][10][11][12] and endothelial cells lining sinusoids. 13 These mesenchymal stem/progenitor cells (MSPCs) express/secrete the cytokines, extracellular matrix proteins, and cell adhesion molecules that support the homing, migration, proliferation, and survival of HSPCs in vitro and in vivo. 8,[14][15][16][17] Given the functional importance of the microenvironment, there has been significant experimentation to test the hypothesis that transplantation of various stromal elements will enhance the engraftment of hematopoietic stem cells. However, despite the unambiguous role for stromal elements in supporting hematopoiesis, and the evidence that transplantation of mesenchymal cells enhances bone formation in patients with mesenchymal stem cell defects, 18 cotransplantation of mesenchymal cells has yielded only modest and variable enhancement to the engraftment of hematopoietic stem cells (HSCs). The use of genetic models that have defects in hematopoietic and/or mesenchymal stem cells may facilitate characterizing the role of MSPCs in supporting hematopoiesis.Fanconi anemia (FA) is a complex recessive inherited disorder caused by mutations in 13 genes whose products interact in a common pathway associated with the homologous recombination repair of DNA damage. [19][20][21][22] Patients with FA are clinically characterized by congenital anomalies, a progressive bone marrow failure, and a high propensity to develop malignancies. [19][20][21][23][24][25][26] Although it is established that FA has defects in the HSC compartment, the effect of loss of FA in other stem cell compartments has received relatively limited attention. In particular, other than variable cytokine production by FA fibroblasts and limited coculture experiments with variable results conducted more than 13 years ago, 24,25,27,28 little information is available on the role of FA genes in influencing mesenchymal lineage functions and fates. However, the fact that patients with FA have characteristic anomalies in the skeletal, renal, and cutaneous tissues, all of which are mesenchymal derived, provides a strong rationale for exploring the role of FA genes in MSPC functions that provide good model systems in vitro and in vivo in syngeneic murine models of FA.In the present study, we investigated the effect of MSPCs in modulating HSPC functions both in vivo and in vitro with the use of a murine model with targeted disruption of the Fancg gene (Fancg Ϫ/Ϫ ), which has been shown to be hypersensitive in vivo to ...

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“…19 Selected Sca1 ϩ c-kit ϩ Lin Ϫ (SCL) cells were cultured in Iscoves Modified Dulbecco media (Gibco-BRL, Gaithersburg, MD) supplemented with 20% fetal calf serum (FCS; Hyclone Laboratories, Logan, UT) at an initial cell density of 10 5 cells/mL in the presence of interleukin 6 (IL-6; 200 U/mL) and stem cell factor (SCF; 100 ng/mL; Peprotech Rocky Hill, NJ). 13,19 …”

Section: Purification and Culture Of Scl Cellsmentioning

confidence: 99%

“…Freshly isolated or cultured SCL cells were fixed in 1% paraformaldehyde 19 and evaluated for apoptosis using a TUNEL (terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridine triphosphate [dUTP] nick end labeling) assay (ApopTag Apoptosis Detection Kit; Intergen, Purchase, NY) as suggested by the manufacturer and analyzed using fluorescence cytometry.…”

Section: Tunel Assaymentioning

confidence: 99%

Ex vivo culture of Fancc-/- stem/progenitor cells predisposes cells to undergo apoptosis, and surviving stem/progenitor cells display cytogenetic abnormalities and an increased risk of malignancy

Beau

Ciccone

et al. 2005

Blood

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Fanconi anemia type C–deficient hematopoietic stem/progenitor cells exhibit aberrant cell cycle control

Cited by 30 publications

References 24 publications

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

Mesenchymal stem/progenitor cells promote the reconstitution of exogenous hematopoietic stem cells in Fancg−/− mice in vivo

Ex vivo culture of Fancc-/- stem/progenitor cells predisposes cells to undergo apoptosis, and surviving stem/progenitor cells display cytogenetic abnormalities and an increased risk of malignancy

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