Loss of FancC Function Results in Decreased Hematopoietic Stem Cell Repopulating Ability

Haneline, Laura S.; Gobbett, Troy A.; Ramani, Rema; Carreau, Madeleine; Buchwald, Manuel; Yöder, Mervin C.; Clapp, D. Wade

doi:10.1203/00006450-199904020-00872

Cited by 86 publications

(147 citation statements)

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“…As expected from previous studies [29,37,40], both Fanca −/− and Fancc −/− mice had a significant decrease in bone marrow repopulating ability as compared to the repopulating ability of WT mice. However, in response to GCSF alone, this decrease in repopulating ability was accompanied by an additional decrease in the proportion of repopulating units mobilized from the bone marrow to the peripheral blood.…”

Section: Discussionsupporting

confidence: 88%

“…The identification of these genes raises the potential of using gene transfer technology to express the functional cDNA in autologous stem cells. The BM hypoplasia commonly observed in FA patients [1] and the reduced repopulating ability of stem cells in mice containing a disruption of the murine homologue of an FA gene [29,30] led to the hypothesis that autologous, geneticallycorrected stem cells would have an engraftment and proliferation advantage.…”

Section: Introductionmentioning

confidence: 99%

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AMD3100 synergizes with G-CSF to mobilize repopulating stem cells in Fanconi anemia knockout mice

Pulliam

Hobson

Ciccone

et al. 2008

Experimental Hematology

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Fanconi anemia (FA) is a heterogeneous inherited disorder characterized by a progressive bone marrow (BM) failure and susceptibility to myeloid leukemia. Genetic correction using gene transfer technology is one potential therapy. A major hurdle in applying this technology in FA patients is the inability of granulocyte colony-stimulating factor (G-CSF) to mobilize sufficient numbers of hematopoietic stem (HSC)/progenitor cells (HPC) from the BM to the PB. Whether the low number of CD34 + cells is a result of BM hypoplasia or an inability of G-CSF to adequately mobilize FA HSC/HPC remains incompletely understood. Here we use competitive repopulation of lethally irradiated primary and secondary recipients to show that in two murine models of FA, AMD3100 synergizes with G-CSF resulting in a mobilization of HSC, whereas G-CSF alone fails to mobilize stem cells even in the absence of hypoplasia.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

AMD3100 synergizes with G-CSF to mobilize repopulating stem cells in Fanconi anemia knockout mice

Pulliam

Hobson

Ciccone

et al. 2008

Experimental Hematology

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“…Specifically, we have shown that the mice demonstrate hypersensitivity to the inhibitory effects of IFN␥ in vitro and in vivo. 9 Haneline et al has recently reported hypersensitivity to IFN␥, TNF␣ and the chemokine MIP1␣ 11 and reduced repopulating potential in FANCC stem cells, 24 a phenomenon that is quite compatible with apoptosis in stem cells or their immediate progeny.…”

Section: Fa and The Apoptotic Phenotypementioning

confidence: 99%

Selective pressure as an essential force in molecular evolution of myeloid leukemic clones: a view from the window of Fanconi anemia

Lensch¹,

Rathbun

Olson

et al. 1999

Leukemia

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“…Given that FA cells are hypersensitive to reactive oxygen species (ROS), 19,37 we therefore tested the hypothesis that ROS levels are increased in KSL cells from Fancd2 Ϫ/Ϫ mice. Double- For personal use only.…”

Section: Resveratrol Treatment Partially Corrected the Hematopoietic mentioning

confidence: 99%

“…16 Notably, in contrast to humans with mutations of these genes, anemia has not been reported in any of these mice, although the bone marrow cells from the well-characterized Fancc Ϫ/Ϫ mice have shown reduced repopulating ability in transplantation experiments. [17][18][19][20] Similar to human FA patients, Fancd2 Ϫ/Ϫ mice have a higher incidence of tumors, a phenotype that occurs rarely in Fancc Ϫ/Ϫ or other models with a deficient FA core-complex gene. 16,21 However, the hematopoietic properties of Fancd2 Ϫ/Ϫ mice have not been fully characterized previously.…”

mentioning

confidence: 99%

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

Zhang

Marquez-Loza

Eaton

et al. 2010

Blood

106

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Progressive bone marrow failure is a major cause of morbidity and mortality in human Fanconi Anemia patients. In an effort to develop a Fanconi Anemia murine model to study bone marrow failure, we found that Fancd2 ؊/؊ mice have readily measurable hematopoietic defects. Fancd2 deficiency was associated with a significant decline in the size of the c-Kit ؉ Sca-1 ؉ Lineage ؊ (KSL) pool and reduced stem cell repopulation and spleen colony-forming capacity. Fancd2 ؊/؊ KSL cells showed an abnormal cell cycle status and loss of quiescence. In addition, the supportive function of the marrow microenvironment was compromised in Fancd2 ؊/؊ mice. Treatment with Sirt1-mimetic and the antioxidant drug, resveratrol, maintained Fancd2 ؊/؊ KSL cells in quiescence, improved the marrow microenvironment, partially corrected the abnormal cell cycle status, and significantly improved the spleen colony-forming capacity of Fancd2 ؊/؊ bone marrow cells. We conclude that Fancd2 ؊/؊ mice have readily quantifiable hematopoietic defects, and that this model is well suited for pharmacologic screening studies. IntroductionFanconi anemia (FA) is a rare, autosomal, recessive genetic disorder associated with severe birth defects, cancer predisposition, and bone marrow failure. Thirteen causative genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCL/PHF9/Pog, FANCJ/BRIP1/BACH1, FANCM/Hef, and FANCN/ PALB2) have been identified and cloned to date, and the encoded proteins are believed to work together in a common DNA damageresponse pathway to maintain genomic integrity and protect the genome from DNA damage induced by cross-linking agents. 1,2 Although deficiency in DNA cross-link repair renders all FA cells susceptible to cross-linking agents, bone marrow is the most affected organ system. Mutations in any of the different FA genes almost universally lead to bone marrow failure, which is the primary cause of mortality in FA. 3 The pathogenesis of bone marrow failure in FA remains elusive. Mutations in several genes involved in DNA damage repair, including Atr, XPD, and Ercc1, caused either hematopoietic stem cell (HSC) loss or impaired HSC function under conditions of stress. [4][5][6] These studies suggest that the maintenance of genome integrity is critical for HSC survival and function. However, the extent to which genotoxicity, resulting from impaired DNA damage repair, contributes to bone marrow failure in FA is unclear. 7 Other pathways associated with hematopoietic failure, such as altered cytokine signaling, may also contribute to FA pathogenesis. 8,9 For example, levels of proapoptotic cytokines tumor necrosis factor-␣ (TNF-␣) and interferon-␥ (IFN-␥) are elevated in FA lymphocytes, bone marrow cells, and FA patient serum samples. 10-12 FA bone marrow cells (at least of the C complementation group) are also hypersensitive to these cytokines and undergo apoptosis when exposed to even low levels of them. [13][14][15] To better understand FA, multiple murine knockout models, includingand Fancl Ϫ/Ϫ m...

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Loss of FancC Function Results in Decreased Hematopoietic Stem Cell Repopulating Ability

Cited by 86 publications

References 0 publications

AMD3100 synergizes with G-CSF to mobilize repopulating stem cells in Fanconi anemia knockout mice

AMD3100 synergizes with G-CSF to mobilize repopulating stem cells in Fanconi anemia knockout mice

Selective pressure as an essential force in molecular evolution of myeloid leukemic clones: a view from the window of Fanconi anemia

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

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