Formal genetics of Fanconi's anemia

Schroeder, Traute M.; Tilgen, D.; Krüger, J.; Vogel, Friedrich

doi:10.1007/bf00295817

Cited by 179 publications

(44 citation statements)

References 49 publications

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“…3,17 Thus there is a theoretical potential of FA patients having an increased incidence for secondary malignancies following myelopreparation with genotoxic agents. Due to the low frequency of FA in the general population 18 and the high incidence of malignant predisposition of FA patients, it is difficult to fully ascertain the risk associated with the genotoxic myelopreparation regimen in patients. However, several studies suggest an increased risk for hematopoietic and nonhematopoietic secondary malignancies [19][20][21][22] after hematopoietic stem cell transplantation in FA patients.…”

Section: Introductionmentioning

confidence: 99%

Continuous in vivo infusion of interferon-gamma (IFN-γ) enhances engraftment of syngeneic wild-type cells in Fanca–/– and Fancg–/– mice

Ciccone

Yang

et al. 2006

Blood

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IntroductionFanconi anemia (FA) is a heterogeneous genetic disorder characterized by a progressive bone marrow aplasia, chromosomal instability, and the acquisition of malignancies. The progressive bone marrow failure in FA and the late developing myeloid malignancies account for 90% of the mortality in FA. 1 Currently, the only cure for the hematopoietic manifestations of FA is HLA-identical allogeneic bone marrow transplantation, a therapy available to only about 30% of patients. 2 Twelve FA complementation types (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, and FANCM) have been identified and the cDNAs of 11 FA genes have been sequenced. [3][4][5][6][7][8][9][10] The identification of these genes raises the potential of using gene transfer technology to express the functional cDNA into autologous stem cells. The bone marrow 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 11,12 led to the hypothesis that autologous, genetically-corrected stem cells would have an engraftment and proliferation advantage. However, ex vivo culture is known to reduce stem cell engraftment in both normal murine and human cells, [13][14][15] and in an initial phase 1 clinical trial in FA patients where myelopreparation was not routinely performed 16 the detection of transduced cells was low in all patients. Furthermore, the most efficient engraftment of transduced cells in the clinical FA trial was observed in a single patient who received nonlethal ionizing radiation. Collectively, these data provide rationale for considering nonmyeloablative therapy prior to transplantation of autologous genetically-corrected stem cells.FA cells exhibit increased chromosomal breaks in response to DNA-damaging agents in vitro. 3,17 Thus there is a theoretical potential of FA patients having an increased incidence for secondary malignancies following myelopreparation with genotoxic agents. Due to the low frequency of FA in the general population 18 and the high incidence of malignant predisposition of FA patients, it is difficult to fully ascertain the risk associated with the genotoxic myelopreparation regimen in patients. However, several studies suggest an increased risk for hematopoietic and nonhematopoietic secondary malignancies [19][20][21][22] after hematopoietic stem cell transplantation in FA patients. For these reasons, a nongenotoxic myelopreparative regimen would be ideal in selecting geneticallycorrected stem cells in vivo.Interferon-gamma (IFN-␥) is a nongenotoxic immunoregulatory lymphokine with a high therapeutic index 23 that has been used to treat a number of malignancies. [24][25][26] Rathbun et al provided the first evidence that murine (Fancc Ϫ/Ϫ ) and human (FANCC) hematopoietic cells were hypersensitive to IFN-␥ via an increase in apoptosis. 27 These results were subsequently confirmed in an independent Fancc Ϫ/Ϫ murine model in vitro and in vivo. 28,29 Previous work indica...

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Section: Introductionmentioning

confidence: 99%

Continuous in vivo infusion of interferon-gamma (IFN-γ) enhances engraftment of syngeneic wild-type cells in Fanca–/– and Fancg–/– mice

Ciccone

Yang

et al. 2006

Blood

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“…[1][2][3][4] Cells from FA patients are hypersensitive to the effects of DNA cross-linking agents, such as mitomycin C and diepoxybutane. 5,6 The disorder is genetically heterogeneous, with at least 7 different complementation groups.…”

Section: Introductionmentioning

confidence: 99%

Functional correction of FA-C cells withFANCC suppresses the expression of interferon γ–inducible genes

Fagerlie

Diaz

Christianson

et al. 2001

Blood

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IntroductionFanconi anemia (FA) is an autosomal recessive disease characterized by progressive bone marrow failure, multiple congenital anomalies, and a high incidence of acute myelogenous leukemia. [1][2][3][4] Cells from FA patients are hypersensitive to the effects of DNA cross-linking agents, such as mitomycin C and diepoxybutane. 5,6 The disorder is genetically heterogeneous, with at least 7 different complementation groups. 7,8 The genes corresponding to group A (FANCA), C (FANCC), E (FANCE), F (FANCF), and G (FANCG) have been cloned. [9][10][11][12][13] Fanconi gene sequences show no significant homology to any known genes, and the functions of their gene products are unknown. 14,15 Hematopoietic precursor cells from children with FA of the C complementation group (FA-C) are excessively apoptotic and hypersensitive to a variety of cytokines known to induce apoptosis, including interferon ␥ (IFN␥). IFN␥ is a cytokine involved in host defense against viral infections and regulation of cell growth. 16 IFN␥ clearly plays a role in hematopoietic suppression and has been implicated in the pathogenesis of acquired aplastic anemia. [16][17][18][19][20][21][22] Cells with inactivating FANCC mutations are hypersensitive to the apoptotic effects of IFN␥, an effect that depends in part on an intact fas/fas-ligand pathway. [23][24][25][26] Specifically, exposure to low doses of IFN␥ in vitro primes a substantial fraction of FA-C progenitor cells to undergo apoptosis after subsequent exposure to fas ligand. Such doses of IFN␥ have no effect on normal hematopoietic progenitor cells. 23,24 Because of the influence of IFN␥ on the fas pathway, we sought to determine whether other IFN␥-inducible genes are hyperactive in FA-C cells. We carried out studies designed to analyze expression of IFN␥-inducible genes known to promote apoptosis and/or mitogenic inhibition in hematopoietic progenitor cells. We describe here studies revealing that the transactivators interferon regulatory factor-1 (IRF-1) and IFNstimulated gene factor 3 gamma subunit (ISGF3␥) and the cyclindependent kinase (cdk) inhibitor p21 WAF1 are expressed at constitutively higher levels in FA-C B lymphoblasts, low-density bone marrow cells (LDBMCs), and murine embryonic fibroblasts (MEFs), compared with cells expressing a normal FANCC. However, these proteins are expressed at normal levels in mature mutant fibroblasts, suggesting some degree of tissue or developmental stage specificity of FANCC function in control of these genes.IFN␥ exerts its effects, at least in part, through the Jak/signal transducer and activator of transcription (STAT) signaling pathway, 27,28 However, FA-C cells are defective in their ability to properly activate STAT1. 29 We show here that up-regulation of IFN␥-inducible genes occurs precisely in those cell types that fail to properly activate STAT1. For this reason, we hypothesized that loss of a STAT1-inducible transcriptional repressor may result in up-regulation of IFN␥-inducible genes in FA-C cells. Indeed, we found expression of the...

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“…94:846-852.) Key words: hematopoiesis * antisense oligonucleotides -DNA damage * chromosome instability * cross-linking agent Fanconi anemia (FA)1 is an autosomal recessive disorder characterized by cellular hypersensitivity to agents that damage DNA, bone marrow failure, diverse congenital anomalies, and a marked increase in the incidence of acute myelogenous leukemia (1,2). Diagnostically, the sine qua non of this disorder is hypersensitivity of FA cells to the clastogenic effects of DNA cross-linking agents such as diepoxybutane and mitomycin C (3,4).…”

Section: Introductionmentioning

confidence: 99%

Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells.

Segal¹,

Magenis²,

Brown³

et al. 1994

J. Clin. Invest.

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Formal genetics of Fanconi's anemia

Cited by 179 publications

References 49 publications

Continuous in vivo infusion of interferon-gamma (IFN-γ) enhances engraftment of syngeneic wild-type cells in Fanca–/– and Fancg–/– mice

Continuous in vivo infusion of interferon-gamma (IFN-γ) enhances engraftment of syngeneic wild-type cells in Fanca–/– and Fancg–/– mice

Functional correction of FA-C cells withFANCC suppresses the expression of interferon γ–inducible genes

Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells.

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