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

Fagerlie, Sara R.; Diaz, Jane; Christianson, Tracy A.; McCartan, Kelli; Keeble, Winifred; Faulkner, Gregory R.; Bagby, Grover C.

doi:10.1182/blood.v97.10.3017

Cited by 42 publications

(39 citation statements)

References 58 publications

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“…Mutant cells exhibit spontaneous chromosomal breakage 38 and increased sensitivity to the development of cytogenetic anomalies on in vitro treatment with cross-linking agents 39 such as MMC 40 and DEB. 41 Additional functions for FA proteins have also been described, including modulation of cytokine-mediated signaling, [42][43][44][45][46][47][48][49][50] responsiveness to oxidative stress, [51][52][53][54][55][56][57] and chromatin remodeling. 58 Moreover, at least 2 members of the FA genes (FANCC and FANCD2) are multifunctional.…”

Section: Genetic Analysis Of a Lymphoblastoid Cell Line From The Samementioning

confidence: 99%

Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia

Lensch¹

2003

Blood

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Myelodysplastic and leukemic stem cell clones that evolve in children and adults with Fanconi anemia universally bear complex cytogenetic abnormalities. The abnormalities are generally recurring deletions or chromosomal loss and involve precisely the same chromosomes with the same frequency as has been described in marrow cells from patients with secondary acute leukemia induced by alkylating agents. Reasoning that acquired Fanconi anemia protein dysfunction might contribute to cytogenetic instability in secondary acute myelogenous leukemia (AML) cells, we analyzed leukemic cells bearing characteristic complex cytogenetic defects obtained from a 68-year-old man whose lymphoblasts showed no evidence of Fanconi anemia. Unlike the lymphoblasts, this myeloid leukemia cell line (UoC-M1) was hypersensitive to mitomycin-C (MMC) and diepoxybutane (DEB) and exhibited a marked decrease in nuclear FANCA, FANCG, and FANCD2-L. Retroviral transduction of FANCA significantly reduced MMC sensitivity but FANCF, FANCG, and FANCC did not. Overexpression of FANCA restored levels of both FANCA and FANCG, whereas overexpression of FANCG or IntroductionA variety of molecular defects have been discovered in patients with myeloproliferative syndromes and acute myelogenous leukemia, many of which result in the activation of autonomous signal transduction pathways for growth and survival. [1][2][3][4][5] Although oncogenic mutations in such pathways are sufficient to induce myeloproliferative disorders in transgenic mice, 2,3 the development of acute leukemia requires additional mutations that ultimately interfere with myeloid differentiation. 6 The risk of this second type of mutation would be necessarily enhanced by cytogenetic instability, a manifestation of which in the leukemic clone would be multiple cytogenetic defects. That such complex cytogenetic defects universally occur in the myeloid leukemic clones of children with Fanconi anemia, a cytogenetic instability syndrome, supports this notion. In fact, because the clonal abnormalities found in this clinical context exactly recapitulate those found in patients with secondary myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), 7,8 and high-risk MDS, 9 we hypothesized that acquired Fanconi anemia (FA) protein dysfunction might serve as a progression factor for the evolution of cytogenetically unstable AML clones, even in patients without hereditary evidence of Fanconi anemia. To test this notion, we examined a variety of AML cells and cell lines, including a cell line from a 68-year-old patient with cytogenetic defects characteristic of secondary AML. The patient's lymphoblasts were normal, but the leukemic cell population exhibited hypersensitivity to mitomycin C, a feature of Fanconi anemia. Nuclear FANCC, FANCG, and FANCA levels were markedly reduced, and retroviral complementation indicated that the leukemic cells exhibited a secondary defect of FANCA function. Because lymphoblasts from this same patient showed normal levels of nuclear Fanconi proteins, we propo...

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Section: Genetic Analysis Of a Lymphoblastoid Cell Line From The Samementioning

confidence: 99%

Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia

Lensch¹

2003

Blood

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“…The lymphoblast lines, JY (normal), HSC536N (FANCC mutant), HSC536/FANCC (corrected), and HSC536/neo (mutant, transduced with vector only), were described previously (29). Murine embryonic fibroblasts (MEFs) were established from Fancc knockout and wild-type mice and transformed, as previously described (26,30,31).…”

Section: Cell Culture and Cytokine Stimulationmentioning

confidence: 99%

“…In addition, differentiation of Th cell subsets is impaired in Tyk2 Ϫ/Ϫ mice (26,27). We sought to determine whether other phenotypic abnormalities observed in Tyk2 Ϫ/Ϫ mice were also present in Fancc Ϫ/Ϫ mice.…”

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“…However, based upon studies on FANCC, there is emerging evidence that individual FA proteins function in other pathways independent of the nuclear complex (3). Of particular relevance to immune function is the role of FANCC in facilitating activation of STAT1 in response to IFN-␥ (25,26). FANCC interacts with STAT1 following stimulation with IFN-␥ and is required for proper docking of STAT1 at the IFN-␥ receptor ␣-chain (IFN-␥R␣).…”

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Impaired Type I IFN-Induced Jak/STAT Signaling in FA-C Cells and Abnormal CD4+ Th Cell Subsets in Fancc−/− Mice

Fagerlie

Koretsky

Torok‐Storb

et al. 2004

The Journal of Immunology

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The Fanconi anemia (FA) group C protein, FANCC, interacts with STAT1 following stimulation with IFN-γ and is required for proper docking of STAT1 at the IFN-γ receptor α-chain (IFN-γRα, IFN-γR1). Consequently, loss of a functional FANCC results in decreased activation of STAT1 following IFN-γ stimulation. Because type I IFN receptors influence the function of type II receptors, and vice versa, we conducted experiments designed to determine whether type I IFN-induced activation of other STAT proteins is compromised in FA-C cells and found that activation of STAT 1, 3, and 5 is diminished in type I IFN-stimulated cells bearing Fancc-inactivating mutations. We also determined that the reduced activation of STATs was accompanied by significant reduction of type I IFN-induced tyrosine kinase 2 and Jak1 phosphorylation. Because tyrosine kinase 2 plays a role in differentiation of Th cells, we quantified cytokine secretion from CD4+ cells and in vitro generated CD4+ Th cell subsets from splenocytes of Fancc null mice to that of heterozygous mice and discovered reduced CD4+ IFN-γ secretion in the Fancc−/− mouse, indicating impaired Th1 differentiation. We suggest that Fancc mutations result in a subtle immunological defect owing to the failure of FANCC to normally support Jak/STAT signaling.

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“…Furthermore, the expression of Egr-1 decreased in FA-A cells as previously observed in lymphoblast cell lines. To assess the specificity of this expression pattern, the mRNA levels of p21, which is highly expressed in FA-C lymphoblast cell lines, 31 were analyzed and found to be increased in FA-A cells compared with control lymphoblasts ( Figure 6B). …”

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Jun N-terminal kinase activity and early growth-response factor-1 gene expression are down-regulated in Fanconi anemia group A lymphoblasts

Pipaón

Casado

Bueren

et al. 2004

Blood

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Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome characterized by cellular sensitivity to genotoxic agents. In recent years, FA proteins have been associated with different molecules involved in signal transduction, which has raised the interest in FA-dependent signaling pathways. Here, we report that the c-Jun N-terminal kinase (JNK) fails to phosphorylate in response to UV radiation and treatment with mitomycin C in FA lymphoblast cells derived from type A patients (FA-A). Furthermore, defective kinase activity seems to be specific for JNK, because extracellular signalregulated kinase (ERK) responded to the proper stimuli in FA-A cells. We also demonstrate that the early growthresponse factor-1 (Egr-1), a JNK downstream target gene that is normally induced by genotoxic stress, is not upregulated in UV IntroductionFanconi anemia (FA) is an autosomal recessive disease characterized by developmental abnormalities, progressive bone marrow failure, and cancer susceptibility. At the cellular level, FA cells are hypersensitive to DNA cross-linking agents such as mitomycin C (MMC) or diepoxybutane. 1,2 FA is a genetically heterogeneous disease, comprising at least 8 complementation groups: FA-A, -B, -C, -D1, -D2, -E, -F and -G, the FA-A group being the most frequently represented in these patients. 3,4 Seven FA-associated genes have been cloned to date, and their products were found to interact with DNA damage-response proteins, including BRCA1, ATM, and NBS1. [5][6][7] In line with this, it has been described that FA proteins may be involved in the process of repairing chromosome defects that occur during homologous recombination. 5 A complex of 5 FA proteins (FANCA, FANCC, FANCE, FANCF, and FANCG) triggers the monoubiquitination of the FANCD2 protein and its interaction with BRCA1 in response to DNA damage. 6 BRCA1 plays an important role in mediating cell cycle arrest, apoptosis, and cellular responses to DNA damage signals. 8,9 Recently it has been shown that BRCA1 is cleaved by caspase-3 during UV-induced apoptosis, which produces a C-terminal fragment that triggers an apoptotic response through activation of c-Jun N-terminal kinase (JNK) and GADD45. 10 Consistently, phosphorylation activity of JNK is abrogated in breast cancer cells after blockade of BRCA1 expression with specific ribozymes, indicating that JNK is a downstream target of BRCA1. 11 Additionally, FANC proteins exhibit functions besides their role in the complex. To this end, a number of FANCC-dependent molecular mechanisms have been suggested to ensure the survival of hematopoietic cells. Notably, FANCC is involved in the activation of signal transducer and activator of transcription-1 (STAT1) through growth factor receptors, 12 it cooperates with heat-shock protein 70 (Hsp70) to suppress the activity of proapoptotic interferon-inducible double-stranded RNA-dependent protein kinase (PKR), 13 and binds to glutathione S-transferase P1-1 (GSTP1), inducing the detoxification of by-products of oxidative stress. 14 Interest...

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

Cited by 42 publications

References 58 publications

Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia

Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia

Impaired Type I IFN-Induced Jak/STAT Signaling in FA-C Cells and Abnormal CD4+ Th Cell Subsets in Fancc−/− Mice

Jun N-terminal kinase activity and early growth-response factor-1 gene expression are down-regulated in Fanconi anemia group A lymphoblasts

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