Nuclear Localization of Fanconi Anemia Protein FANCA Is Regulated by Hsc70/Hsp90 Chaperone Machinery.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2835-2835
Author(s):  
Tsukasa Oda ◽  
Hidenobu Miyaso ◽  
Takayuki Yamashita
Keyword(s):  
Nuclear Localization ◽  
Fanconi Anemia ◽  
Subcellular Distribution ◽  
Molecular Mechanisms ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Specific Inhibitor ◽  
Current Evidence ◽  
Core Complex ◽  
Hsp90 Chaperone

Abstract Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, cancer susceptibility and cellular hypersensitivity to DNA crosslinkers such as mitomycin C (MMC). Current evidence indicates that formation of a nuclear multiprotein complex (core complex) including six FA proteins FANCA/C/E/F/G/L is essential for FANCL/PHF9 ubiquitin ligase-mediated activation of FANCD2 into a monoubiquinated form, which participates in BRCA1 and FANCD1/BRCA2-mediated DNA repair (the FA/BRCA pathway). Subcellular distribution of FANCA plays a crucial role in the regulation of the FA/BRCA pathway. However, the underlying molecular mechanisms are not fully understood. To address this issue, we tried to identify FANCA-associated proteins. To this end, Flag-FANCA ectopically expressed in HeLa cells was immunopurified from the cytoplasmic fraction, using anti-Flag antibody-conjugated sepharose beads. Analysis of the immune complex on SDS polyacrylamide gel electrophoresis revealed that several proteins of Mr. 60–70 kD specifically associated with Flag-FANCA. These proteins were identified as FANCG and Hsc (heat shock cognate protein) 70 by LC-MS/MS. Immunoblot analysis showed that FANCA associated with Hsp90 as well as Hsc70. Hsc70 is an ATP-dependent molecular chaperone highly homologous to Hsp70 and often cooperates with Hsp90 to form a chaperone machinery involved in the regulation of diverse protein functions. Patient-derived FANCA mutants failed to bind FANCC but associated with larger amounts of Hsc70 than wt-FANCA, indicating that the interaction between FANCA and Hsc70 is not mediated by FANCC, as suggested by previous observations of the interaction of FANCC with Hsp70. To study the role of Hsc70 and Hsp90 in the regulation of FANCA, we examined effects of a dominant-negative (dn) form of Hsc70 with inactivated ATPase activity, and a specific inhibitor of Hsp90, 17-AAG (a geldanamycin analog). Overexpression of dn-Hsc70 inhibited nuclear localization of FANCA and inhibited its core complex formation, whereas wt-Hsc70 did not. 17-AAG induced cytoplasmic distribution and proteosomal degradation of FANCA and suppressed FANCD2 mono-ubiquitination. Taken together, these results suggest that Hsc70/Hsp90 chaperone machinery interacts with FANCA and regulates its subcellular distribution and stability, thereby controlling activation of the FA/BRCA pathway.

scholarly journals Towards a Molecular Understanding of the Fanconi Anemia Core Complex

Anemia ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Charlotte Hodson ◽  
Helen Walden
Keyword(s):  
Fanconi Anemia ◽  
Molecular Mechanisms ◽  
Genome Instability ◽  
Genetic Disorder ◽  
Single Gene ◽  
Main Function ◽  
Core Complex ◽  
Interstrand Crosslinks ◽  
Dna Interstrand Crosslinks ◽  
Interstrand Crosslinking

Fanconi Anemia (FA) is a genetic disorder characterized by the inability of patient cells to repair DNA damage caused by interstrand crosslinking agents. There are currently 14 verified FA genes, where mutation of any single gene prevents repair of DNA interstrand crosslinks (ICLs). The accumulation of ICL damage results in genome instability and patients having a high predisposition to cancers. The key event of the FA pathway is dependent on an eight-protein core complex (CC), required for the monoubiquitination of each member of the FANCD2-FANCI complex. Interestingly, the majority of patient mutations reside in the CC. The molecular mechanisms underlying the requirement for such a large complex to carry out a monoubiquitination event remain a mystery. This paper documents the extensive efforts of researchers so far to understand the molecular roles of the CC proteins with regard to its main function in the FA pathway, the monoubiquitination of FANCD2 and FANCI.

scholarly journals Phase II Study of Eltrombopag in Subjects with Fanconi Anemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3753-3753
Author(s):  
Daisuke Araki ◽  
Ma Evette Barranta ◽  
Fariba Chinian ◽  
Julie Erb-Alvarez ◽  
Thomas Winkler ◽  
...  
Keyword(s):  
Phase Ii ◽  
Fanconi Anemia ◽  
Platelet Transfusion ◽  
Phase Ii Study ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Study Entry ◽  
Extension Phase ◽  
Therapeutic Modality ◽  
Hematopoietic Stem

Background. Fanconi anemia (FA) is a rare genetic disorder that often presents with progressive bone marrow failure (BMF) due to an impaired DNA damage response and chronic exposure to elevated levels of proinflammatory cytokines. To date, hematopoietic stem/progenitor cell (HSPC) transplantation remains the only curative treatment for FA-associated BMF. However, donor availability, graft failure, and FA-specific transplant toxicities remain significant hurdles. Androgens have been successfully used but side effects often prevent prolonged therapy. Attempts at genetic correction of FA are underway but clinical efficacy has not yet been demonstrated. In this clinical trial, we investigate whether eltrombopag (EPAG), an FDA-approved mimetic of thrombopoietin that promotes trilineage hematopoiesis in subjects with acquired BMF (Olnes, NEJM 2012; Townsley, NEJM 2017), may offer a novel therapeutic modality for subjects with FA. Our pre-clinical studies indicate that EPAG evades blockade of signal transduction from c-MPL induced by inflammatory cytokines (Alvarado, Blood 2019). Additionally, we found that EPAG enhances DNA repair activity in human HSPCs (Guenther, Exp Hematol 2019). Thus, EPAG may positively influence two of the main known mechanisms leading to BMF in FA. Study Design. This is a non-randomized, phase II study of EPAG given to subjects with FA (NCT03204188). Subjects receive EPAG for 6 months at an oral daily dose adjusted for age and ethnicity. Subjects who cannot tolerate the medication or fail to respond by 6 months are taken off study drug. Subjects who respond at 6 months are invited in the extension phase for an additional 3 years. They continue on the same dose of EPAG until they reach robust count criteria (platelets > 50K/μL, hemoglobin (Hgb) > 10 g/dL in the absence of transfusions, and absolute neutrophil count (ANC) > 1K/uL for > 8 weeks) or until they reach steady state response (defined as stable counts for 6 months). Drug dose is tapered slowly to the lowest dose that maintains a stable platelet count and eventually discontinued until they meet off study criteria or the study is closed. Eligibility Assessment. Inclusion criteria: (1) Confirmed diagnosis of FA by a biallelic mutation in a known FANC gene and/or by positive chromosome breakage analysis in lymphocytes and/or skin fibroblasts; (2) One or more of the following cytopenias: platelets ≤ 30K/μL or platelet transfusion dependence in the 8 weeks prior to study entry, ANC ≤ 500/μL, Hgb ≤ 9.0 g/dL or red blood cell (RBC) transfusion dependence in the 8 weeks prior to study entry; (3) Failed or declined treatment with androgens; 4) Age > 4 years. Exclusion criteria: (1) Evidence of MDS or AML; (2) Cytogenetic abnormalities associated with poor prognosis in FA; (3) Known biallelic mutations in BRCA2; (4) Active malignancy or likelihood of recurrence of malignancies within 12 months; (5) Treatment with androgens ≤ 4 weeks prior to initiating EPAG. Primary Endpoints. The primary efficacy endpoint is the proportion of drug responders at 6 months. Response to EPAG is defined by one or more of the following criteria: (1) Platelets increase by 20K/μL above baseline, or platelet transfusion independence; (2) Hgb increase by > 1.5g/dL or a reduction in the units of RBC transfusions by at least 50%; (3) At least a 100% increase in ANC for subjects with a pretreatment ANC of < 0.5 x 109/L, or an ANC increase > 0.5 x 109/L. The primary safety endpoint is the toxicity profile assessed at 6 months using the CTCAE criteria. Sample Size and Statistical Methods. Simon's Two-Stage Minimax Design is used, with a response probability of ≤ 20% to terminate the treatment. In the first stage, 12 subjects will be accrued. The study will be stopped if no more than 2 subjects respond to the treatment within 6 months. If 3 or more subjects respond within 6 months in the first stage, then an additional 13 subjects will be accrued, for a total of 25 subjects. Enrollment. Two subjects have been enrolled to date. No drug-related adverse events have been observed. Subject #1 (7YO female) did not respond to 6 months of EPAG, likely due to limited HSPC reserve in the context of profound cytopenias (ANC = 100/µL, Hgb = 6g/dL, Plt = 0K/µL). In contrast, subject #2 (49YO female) showed response to EPAG at 3 months and will continue on the extension phase of the study. Conclusion. This study will provide important clinical information on safety and efficacy of EPAG in subjects with FA. Disclosures Winkler: Agios: Employment.

Phenotypic correction of Fanconi anemia group C knockout mice

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 700-704 ◽  
Author(s):  
Kimberly A. Gush ◽  
Kai-Ling Fu ◽  
Markus Grompe ◽  
Christopher E. Walsh
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Mitomycin C ◽  
Fanconi Anemia ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Hematopoietic Stem ◽  
Marrow Cells

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, congenital anomalies, and a predisposition to malignancy. FA cells demonstrate hypersensitivity to DNA cross-linking agents, such as mitomycin C (MMC). Mice with a targeted disruption of the FANCC gene (fancc −/− nullizygous mice) exhibit many of the characteristic features of FA and provide a valuable tool for testing novel therapeutic strategies. We have exploited the inherent hypersensitivity offancc −/− hematopoietic cells to assay for phenotypic correction following transfer of the FANCC complementary DNA (cDNA) into bone marrow cells. Murine fancc −/− bone marrow cells were transduced with the use of retrovirus carrying the humanfancc cDNA and injected into lethally irradiated recipients. Mitomycin C (MMC) dosing, known to induce pancytopenia, was used to challenge the transplanted animals. Phenotypic correction was determined by assessment of peripheral blood counts. Mice that received cells transduced with virus carrying the wild-type gene maintained normal blood counts following MMC administration. All nullizygous control animals receiving MMC exhibited pancytopenia shortly before death. Clonogenic assay and polymerase chain reaction analysis confirmed gene transfer of progenitor cells. These results indicate that selective pressure promotes in vivo enrichment offancc-transduced hematopoietic stem/progenitor cells. In addition, MMC resistance coupled with detection of the transgene in secondary recipients suggests transduction and phenotypic correction of long-term repopulating stem cells.

scholarly journals The Fanconi Anemia Proteins FAA and FAC Function in Different Cellular Compartments to Protect Against Cross-Linking Agent Cytotoxicity

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2229-2236 ◽  
Author(s):  
Frank A.E. Kruyt ◽  
Hagop Youssoufian
Keyword(s):  
Nuclear Localization ◽  
Fanconi Anemia ◽  
Nuclear Export ◽  
Mammalian Cells ◽  
Bone Marrow Failure ◽  
Cross Linking ◽  
Disease Genes ◽  
Macromolecular Complex ◽  
Subcellular Compartment ◽  
Nuclear Localization Signals

Abstract Fanconi anemia (FA) is an autosomal recessive disease characterized by chromosomal instability, bone marrow failure, and a high risk of developing malignancies. Although the disorder is genetically heterogeneous, all FA cells are defined by their sensitivity to the apoptosis-inducing effect of cross-linking agents, such as mitomycin C (MMC). The cloned FA disease genes, FAC and FAA, encode proteins with no homology to each other or to any known protein. We generated a highly specific antibody against FAA and found the protein in both the cytoplasm and nucleus of mammalian cells. By subcellular fractionation, FAA is also associated with intracellular membranes. To identify the subcellular compartment that is relevant for FAA activity, we appended nuclear export and nuclear localization signals to the carboxy terminus of FAA and enriched its localization in either the cytoplasm or the nucleus. Nuclear localization of FAA was both necessary and sufficient to correct MMC sensitivity in FA-A cells. In addition, we found no evidence for an interaction between FAA and FAC either in vivo or in vitro. Together with a previous finding that FAC is active in the cytoplasm but not in the nucleus, our results indicate that FAA and FAC function in separate subcellular compartments. Thus, FAA and FAC, if functionally linked, are more likely to be in a linear pathway rather than form a macromolecular complex to protect against cross-linker cytotoxicity.

Coordinated Chromatin-Association of Fanconi Anemia Network Proteins Requires Replication-Coupled DNA Damage Recognition.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 723-723
Author(s):  
Alexandra Sobeck ◽  
Stacie Stone ◽  
Bendert deGraaf ◽  
Vincenzo Costanzo ◽  
Johan deWinter ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
S Phase ◽  
Dependent Manner ◽  
Core Complex ◽  
Damage Response ◽  
Crosslinking Agents

Abstract Fanconi anemia (FA) is a genetic disorder characterized by hypersensitivity to DNA crosslinking agents and diverse clinical symptoms, including developmental anomalies, progressive bone marrow failure, and predisposition to leukemias and other cancers. FA is genetically heterogeneous, resulting from mutations in any of at least eleven different genes. The FA proteins function together in a pathway composed of a mulitprotein core complex that is required to trigger the DNA-damage dependent activation of the downstream FA protein, FANCD2. This activation is thought to be the key step in a DNA damage response that functionally links FA proteins to major breast cancer susceptibility proteins BRCA1 and BRCA2 (BRCA2 is FA gene FANCD1). The essential function of the FA proteins is unknown, but current models suggest that FA proteins function at the interface between cell cycle checkpoints, DNA repair and DNA replication, and are likely to play roles in the DNA damage response during S phase. To provide a platform for dissecting the key functional events during S-phase, we developed cell-free assays for FA proteins based on replicating extracts from Xenopus eggs. We identified the Xenopus homologs of human FANCD2 (xFANCD2) and several of the FA core complex proteins (xCCPs), and biochemically characterized these proteins in replicating cell-free extracts. We found that xCCPs and a modified isoform of xFANCD2 become associated with chromatin during normal and disrupted DNA replication. Blocking initiation of replication with geminin demonstrated that association of xCCPs and xFANCD2 with chromatin occurs in a strictly replication-dependent manner that is enhanced following DNA damage by crosslinking agents or by addition of aphidicolin, an inhibitor of replicative DNA polymerases. In addition, chromatin binding of xFANCD2, but not xBRCA2, is abrogated when xFANCA is quantitatively depleted from replicating extracts suggesting that xFANCA promotes the loading of xFANCD2 on chromatin. The chromatin-association of xFANCD2 and xCCPs is diminished in the presence of caffeine, an inhibitor of checkpoint kinases. Taken together, our data suggest a model in which the ordered loading of FA proteins on chromatin is required for processing a subset of DNA replication-blocking lesions that are resolved during late stages of replication.

scholarly journals Deficiency of the c-JUN Inhibitor DACH1 in FA Macrophages Accounts for the Cytokine Overproduction Phenotype

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1002-1002
Author(s):  
Michael Garbati ◽  
Grover C. Bagby
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Inflammatory Cytokines ◽  
Fanconi Anemia ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Mononuclear Phagocytes ◽  
Normal Cells

Abstract The inflammatory cytokines TNFα and IL-1β contribute to the bone marrow failure phenotype in Fanconi anemia (FA) as well as to clonal evolution to MDS and AML. Mononuclear phagocytes deficient in FANCA or FANCC overproduce these cytokines in response to toll-like receptor agonists (TLRa), but the precise molecular mechanisms by which FA proteins suppress cytokine production remains enigmatic. We show here that pretreatment of control macrophages with interferon (IFN) α enhances (by 3-fold) TLRa-induced production of both TNFα and IL-1β. FANCC-deficient cells produce more of these proteins (by 3-fold) after exposure to TLRa alone and IFNα does not enhance production of these cytokines. We therefore hypothesized that TLR stimulation of FANCC-deficient cells activates an IFNα-like pathway, one constrained by FANCC in normal cells. To test this notion, we performed gene expression microarray analysis (Affymetrix HTA 2.0) using RNA from FANCC-deficient (T-shFC) and control (T-shNT) THP-1 human mononuclear phagocytes treated with IFNα, the TLR7/8 agonist R848, or a combination of IFNα plus R848. We found that treatment of T-shFC cells with R848 alone was sufficient to enhance expression of 49 genes that were activated by IFNα in control cells. Thirteen of these genes were not induced by R848 in control cells but were induced by R848 in T-shFC cells (one of which, IFNgamma-inducible protein 30 (IFI30), is known to be overexpressed in Fancd2 -/- progenitor cells). These results support our hypothesis that FANCC functions normally to constrain IFNα pathway activation in TLRa-activated macrophages. Of greater functional importance vis-à-vis cytokine production, DACH1 mRNA was suppressed by 11-fold and DACH1 protein was barely detectable in FANCC-deficient cells under all conditions when compared to control cells. DACH1 is known to bind to and suppress the activities of a variety of transcription factors, notably c-JUN in fibroblasts. We tested the hypothesis that DACH1 deficiency is sufficient to account for the TLRa hypersensitivity of FA macrophages using gain- and loss-of-function studies. Knockdown of DACH1 in control (T-shNT) macrophages resulted in a 7-fold enhancement of R848-induced TNFα production, increased c-JUN protein (1.6-fold) and c-JUN phosphorylation (2.6-fold). Reporter gene expression (secreted embryonic alkaline phosphatase [SEAP]) from constructs containing both AP-1 and NF-κB sites was activated by DACH1 knockdown but deletion of the AP-1 site completely abrogated activation. Results of gain-of-function experiments with wild-type and mutant DACH1 cDNA sequences now taking place will be reported. Taken together, these results suggest that FANCC directly or indirectly enhances ground-state expression of DACH1 and thereby suppresses the TLR pathway in normal cells specifically by inhibiting R848-dependent activation of c-JUN. Conversely, loss of DACH1 expression in FANCC-deficient cells leads to unconstrained c-JUN activity, resulting in overproduction inflammatory cytokines. In light of the contribution of such cytokines to both bone marrow failure and clonal evolution, activation of DACH1 gene expression is a rational therapeutic objective in the management of patients with Fanconi anemia and is worthy of investigating in preclinical (animal) models. Disclosures No relevant conflicts of interest to declare.

Gender-related differences in the oxidant state of cells in Fanconi anemia heterozygotes

2011 ◽  
Vol 392 (7) ◽  
Author(s):  
Sandra Petrovic ◽  
Andreja Leskovac ◽  
Jelena Kotur-Stevuljevic ◽  
Jelena Joksic ◽  
Marija Guc-Scekic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Significant Difference ◽  
Heterozygous Carriers ◽  
Male Carriers ◽  
Female Carriers

Abstract Fanconi anemia (FA) is a rare cancer-prone genetic disorder characterized by progressive bone marrow failure, chromosomal instability and redox abnormalities. There is much biochemical and genetic data, which strongly suggest that FA cells experience increased oxidative stress. The present study was designed to elucidate if differences in oxidant state exist between control, idiopathic bone marrow failure (idBMF) and FA cells, and to analyze oxidant state of cells in FA heterozygous carriers as well. The results of the present study confirm an in vivo prooxidant state of FA cells and clearly indicate that FA patients can be distinguished from idBMF patients based on the oxidant state of cells. Female carriers of FA mutation also exhibited hallmarks of an in vivo prooxidant state behaving in a similar manner as FA patients. On the other hand, the oxidant state of cells in FA male carriers and idBMF families failed to show any significant difference vs. controls. We demonstrate that the altered oxidant state influences susceptibility of cells to apoptosis in both FA patients and female carriers. The results highlight the need for further research of the possible role of mitochondrial inheritance in the pathogenesis of FA.

scholarly journals Evidence for subcomplexes in the Fanconi anemia pathway

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 2072-2080 ◽  
Author(s):  
Annette L. Medhurst ◽  
El Houari Laghmani ◽  
Jurgen Steltenpool ◽  
Miriam Ferrer ◽  
Chantal Fontaine ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Protein Interactions ◽  
Congenital Abnormalities ◽  
Bone Marrow Failure ◽  
Direct Interaction ◽  
Molecular Architecture ◽  
Cross Link ◽  
Core Complex ◽  
Downstream Target ◽  
Nuclear Complex

AbstractFanconi anemia (FA) is a genomic instability disorder, clinically characterized by congenital abnormalities, progressive bone marrow failure, and predisposition to malignancy. Cells derived from patients with FA display a marked sensitivity to DNA cross-linking agents, such as mitomycin C (MMC). This observation has led to the hypothesis that the proteins defective in FA are involved in the sensing or repair of interstrand cross-link lesions of the DNA. A nuclear complex consisting of a majority of the FA proteins plays a crucial role in this process and is required for the monoubiquitination of a downstream target, FANCD2. Two new FA genes, FANCB and FANCL, have recently been identified, and their discovery has allowed a more detailed study into the molecular architecture of the FA pathway. We demonstrate a direct interaction between FANCB and FANCL and that a complex of these proteins binds FANCA. The interaction between FANCA and FANCL is dependent on FANCB, FANCG, and FANCM, but independent of FANCC, FANCE, and FANCF. These findings provide a framework for the protein interactions that occur “upstream” in the FA pathway and suggest that besides the FA core complex different subcomplexes exist that may have specific functions other than the monoubiquitination of FANCD2.

scholarly journals The Fanconi Anemia Proteins FAA and FAC Function in Different Cellular Compartments to Protect Against Cross-Linking Agent Cytotoxicity

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2229-2236 ◽  
Author(s):  
Frank A.E. Kruyt ◽  
Hagop Youssoufian
Keyword(s):  
Nuclear Localization ◽  
Fanconi Anemia ◽  
Nuclear Export ◽  
Mammalian Cells ◽  
Bone Marrow Failure ◽  
Cross Linking ◽  
Disease Genes ◽  
Macromolecular Complex ◽  
Subcellular Compartment ◽  
Nuclear Localization Signals

Fanconi anemia (FA) is an autosomal recessive disease characterized by chromosomal instability, bone marrow failure, and a high risk of developing malignancies. Although the disorder is genetically heterogeneous, all FA cells are defined by their sensitivity to the apoptosis-inducing effect of cross-linking agents, such as mitomycin C (MMC). The cloned FA disease genes, FAC and FAA, encode proteins with no homology to each other or to any known protein. We generated a highly specific antibody against FAA and found the protein in both the cytoplasm and nucleus of mammalian cells. By subcellular fractionation, FAA is also associated with intracellular membranes. To identify the subcellular compartment that is relevant for FAA activity, we appended nuclear export and nuclear localization signals to the carboxy terminus of FAA and enriched its localization in either the cytoplasm or the nucleus. Nuclear localization of FAA was both necessary and sufficient to correct MMC sensitivity in FA-A cells. In addition, we found no evidence for an interaction between FAA and FAC either in vivo or in vitro. Together with a previous finding that FAC is active in the cytoplasm but not in the nucleus, our results indicate that FAA and FAC function in separate subcellular compartments. Thus, FAA and FAC, if functionally linked, are more likely to be in a linear pathway rather than form a macromolecular complex to protect against cross-linker cytotoxicity.

scholarly journals Oral Squamous Cell Carcinoma in a Patient with Fanconi Anemia

2021 ◽  
Vol 2021 ◽  
pp. 1-4
Author(s):  
Milla Huuhka ◽  
Aaro Turunen
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Treatment Options ◽  
Skin Lesions ◽  
Increased Risk

Fanconi anemia (FA) is a rare autosomal recessive genetic disorder characterized by different types of malformations, skin lesions, bone marrow failure, and increased risk for both hematological malignancies and solid tumors, especially head and neck squamous cell carcinomas (HNSCC). FA patients may also display a low tolerance to oncologic treatments. The authors present a case of mandibular squamous cell carcinoma in a young FA patient. Because of the aggressive nature of the SCC and complex treatment options, we recommend a strict lifelong follow-up for all FA patients to detect early changes in the oral mucosa.

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