Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia

Müller, Lars; Williams, David A.

doi:10.1016/j.mrfmmm.2009.03.010

Cited by 28 publications

(25 citation statements)

References 107 publications

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“…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][11][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.…”

Section: Fancd1/brca2 Fancd2 Fance Fancf Fancg/xrcc9 Fanci Fancmentioning

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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Section: Fancd1/brca2 Fancd2 Fance Fancf Fancg/xrcc9 Fanci Fancmentioning

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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“…5,[8][9][10][11] Hematopoietic stem cell transplantation is the current treatment in FA to cure aplastic anemia or MDS and to prevent transformation into leukemia. 12,13 It has to be carefully considered on clinical and biologic criteria, which include the age, severity of the cytopenia, significant BM dysplasia, excess of blast cells, cytogenetic abnormalities, and immunologic compatibility with the donor.…”

Section: Introductionmentioning

confidence: 99%

Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions

Quentin

Cuccuini

Ceccaldi

et al. 2011

Blood

161

147

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Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic anemia (n ‫؍‬ 20), MDS (n ‫؍‬ 18), AML (n ‫؍‬ 11), or no BM abnormality (n ‫؍‬ 8). BM samples were analyzed by karyotype, high-density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q؉ (44.8%), 3q؉ (41.4%), ؊7/7q (17.2%), and 11q؊ (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBP␣ mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q؉, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure. (Blood. 2011;117(15):e161-e170)

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“…Jr. Gregory et al, 2001;M. Gross et al, 2002;Hirschhorn, 2003;Lo Ten Foe et al, 1997;Mankad et al, 2006;Müller & Williams, 2009;Notini et al, 2008;Piotrowski et al, 2008;L. Song, 2009;Wada et al, 2001Wada et al, , 2003Waisfisz et al, 1999;Youssoufian & Pyeritz, 2002).…”

Section: A Possible Approach For Gene Therapy Of Some Genetic Diseasesunclassified

Gene Therapy of Some Genetic Diseases by Transferring Normal Human Genomic DNA into Somatic Cells and Stem Cells from Patients

Song¹

2011

Non-Viral Gene Therapy

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Finding the needle in the hay stack: Hematopoietic stem cells in Fanconi anemia

Cited by 28 publications

References 107 publications

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

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

Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions

Gene Therapy of Some Genetic Diseases by Transferring Normal Human Genomic DNA into Somatic Cells and Stem Cells from Patients

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