Individualized risks of first adverse events in patients with Fanconi anemia

Blood ◽  
2004 ◽  
Vol 104 (2) ◽  
pp. 350-355 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Yi Huang ◽  
Blanche P. Alter
Keyword(s):  
Fanconi Anemia ◽  
Cumulative Incidence ◽  
Congenital Abnormality ◽  
Risk Group ◽  
Bone Marrow Failure ◽  
Significant Risk ◽  
Risk Groups ◽  
Hematopoietic Stem ◽  
Prognostic Groups ◽  
Autosomal Recessive Condition

Abstract Fanconi anemia (FA) is an autosomal recessive condition associated with bone marrow failure (BMF) leading to death or hematopoietic stem cell transplantation, acute myeloid leukemia (AML), and solid tumors (STs). It is unclear which patients are most likely to develop each outcome. From a cohort of 144 North American patients with FA, we calculated individualized risks of each outcome, given the presence or absence of readily diagnosed congenital abnormalities that occur frequently in FA. Abnormal radii and a 5-item congenital abnormality score were significant risk factors for BMF. The cumulative incidence of BMF by age 10 years varied from 18% in the lowest BMF risk group to 83% in the highest. Because of competing risks, patients in the lowest BMF risk group were most likely to live long enough to develop AML or ST, and, conversely, patients in the highest BMF risk group were least likely to live long enough to develop AML or ST. By age 40, the cumulative incidence of ST ranged from 0.6% to 29% in the highest and lowest BMF risk groups, respectively. Abnormal radii are the strongest predictor of early BMF in FA; a congenital abnormality score separates patients with normal radii into distinct prognostic groups. (Blood. 2004;104:350-355)

Cancer incidence in persons with Fanconi anemia

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 822-826 ◽  
Author(s):  
Philip S. Rosenberg ◽  
Mark H. Greene ◽  
Blanche P. Alter
Keyword(s):  
Bone Marrow ◽  
Solid Tumors ◽  
Fanconi Anemia ◽  
Solid Tumor ◽  
Cumulative Incidence ◽  
Bone Marrow Failure ◽  
Adverse Outcomes ◽  
Relative Risks ◽  
Autosomal Recessive Condition ◽  
Progressive Pancytopenia

Abstract Fanconi anemia (FA) is an autosomal recessive condition associated with congenital abnormalities, progressive pancytopenia, and a predisposition to leukemia and solid tumors. We studied a retrospective cohort of North American patients with FA. We calculated relative risks of cancer compared to the general population and cause-specific hazards of the first major adverse outcomes of FA: bone marrow transplantation (BMT) for marrow complications, acute myeloid leukemia (AML), solid tumors, or death from bone marrow failure. We also estimated the cumulative incidence of each adverse event in the presence of the competing risks. Among 145 patients with FA, 9 developed leukemia and 14 developed a total of 18 solid tumors. The ratio of observed to expected cancers (O/E ratio) was 50 for all cancers, 48 for all solid tumors, and 785 for leukemia; these increased risks were statistically significant. The highest solid tumor O/E ratios were 4317 for vulvar cancer, 2362 for esophageal cancer, and 706 for head and neck cancer. Cause-specific hazards of both death and AML peaked at 1%/y in teenage years; the hazard of BMT peaked at 4%/y at age 7. In contrast, the hazard of a solid tumor approached 8%/y by age 40 years. The cumulative incidence to age 48 was 10% for leukemia, 11% for death from marrow failure, 29% for a solid tumor, and 43% for BMT. The risk of a solid tumor may become even higher as death from aplastic anemia is reduced and as patients survive longer after BMT.

Cancer Risks in Fanconi Anemia: Experience of the German Fanconi Anemia (GEFA) Registry.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 995-995
Author(s):  
Philip S. Rosenberg ◽  
Blanche P. Alter ◽  
Wolfram Ebell
Keyword(s):  
Bone Marrow ◽  
Solid Tumors ◽  
Fanconi Anemia ◽  
North American ◽  
Cumulative Incidence ◽  
Age Of Onset ◽  
Bone Marrow Failure ◽  
Significant Risk ◽  
North American Population ◽  
Increased Risk

Abstract OBJECTIVE: Acute Myeloid Leukemia (AML) and solid tumors (ST) occur frequently in Fanconi Anemia (FA). Our objective was to characterize the age of onset of cancer and identify any neoplasms occurring in excess. METHODS: We analyzed data from the German Fanconi Anemia (GEFA) Registry, a retrospective cohort. For competing adverse events of bone marrow failure (BMF), AML, and ST, we determined cause-specific hazards and cumulative incidence curves. We calculated the ratio of observed to expected cancers (O/E ratio) in GEFA compared to age- and sex-matched persons from the general North American population. We studied outcomes after bone marrow transplantation (BMT) using survival analysis. RESULTS: In GEFA, 182 patients contributed 2548 person-years of observation prior to BMT; 63 had BMF as the first adverse event, 15 had AML, and 10 had ST. The cumulative incidence by age 50 was 48% for BMF and 29% for ST. The cumulative incidence by age 20 was 9% for AML. The hazard of BMF peaked at 4%/y at age 10. The hazard of AML increased to 1.6%/y at age 20. The hazard of ST increased from 1%/y at age 20, to 5%/y at age 40, to ~10%/y at age 50. The O/E ratio was 45 for all cancers, 24 for all solid tumors, and 926 for AML; these increased risks were statistically significant. Significantly elevated O/E ratios were observed for esophagus (6346), vulva (2436), oral cavity and pharynx (121), breast (34), and brain (23) cancers. Forty-eight patients had BMT prior to cancer. Subsequently, there were 20 deaths and 3 malignancies in 216 person-years. The 3 malignancies (tongue, liver, and esophagus) occurred 2, 16, and 17 years after mismatched, matched, and matched transplant at ages 13, 23, and 34, respectively. The age-specific hazard of ST was 3.8-fold higher in transplanted versus untransplanted patients; this increased risk was not significant (P = 0.11). During 2000–2004, none of 5 patients with matched, and 3 of 18 patients with mismatched donors, died during the period from 0 – 6 months. In patients with matched donors, acute and chronic GVH were significant risk factors for death beyond 6 months. CONCLUSIONS: Absolute and relative risks of cancer in GEFA are quantitatively similar to previously reported estimates from the North American Survey. Outcomes after transplantation in GEFA are comparable to the Hôpital St Louis Cohort. Our prior observation that FA patients who survive BMF are at extraordinary risk of specific ST has been replicated.

scholarly journals ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ADULT PATIENTS WITH FANCONI ANEMIA.

2016 ◽  
Vol 8 ◽  
pp. 2016054 ◽  
Author(s):  
Hosein Kamranzadeh fumani ◽  
Mohammad Zokaasadi ◽  
Amir Kasaeian ◽  
Kamran Alimoghaddam ◽  
Asadollah Mousavi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Term Survival ◽  
Hematopoietic Stem

Background & objectives: Fanconi anemia (FA) is a rare genetic disorder caused by an impaired DNA repair mechanism which leads to an increased tendency toward malignancies and progressive bone marrow failure. The only curative management available for hematologic abnormalities in FA patients is hematopoietic stem cell transplantation (HSCT). This study aimed to evaluate the role of HSCT in FA patients.Methods: Twenty FA patients with ages of 16 or more who underwent HSCT between 2002 and 2015 enrolled in this study. All transplants were allogeneic and the stem cell source was peripheral blood and all patients had a full HLA-matched donor.Results: Eleven patients were female and 9 male (55% and 45%). Mean age was 24.05 years. Mortality rate was 50% (n=10) and the main cause of death was GVHD. Survival analysis showed an overall 5-year survival of 53.63% and 13 year survival of 45.96 % among patients.Conclusion: HSCT is the only curative management for bone marrow failure in FA patients and despite high rate of mortality and morbidity it seems to be an appropriate treatment with an acceptable long term survival rate for adolescent and adult group.

scholarly journals CRP and ferritin in addition to the EASIX score predict CAR-T–related toxicity

2021 ◽  
Vol 5 (14) ◽  
pp. 2799-2806
Author(s):  
Uri Greenbaum ◽  
Paolo Strati ◽  
Rima M. Saliba ◽  
Janet Torres ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
B Cell Lymphoma ◽  
Risk Groups ◽  
Endothelial Activation ◽  
Stress Index ◽  
Cell Transplant ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Laboratory Parameters ◽  
Car T

Abstract The Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study’s objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T–related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration.

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.

scholarly journals Efficacy and Safety of a FLAG-Sequential Regimen Followed By Hematopoietic Stem Cell Transplantation for Myelodysplasia or Acute Leukemia in Fanconi Anemia: A Franco-Brazilian Report

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2498-2498
Author(s):  
Pierre-Edouard Debureaux ◽  
Flore Sicre de Fontbrune ◽  
Carmem M. S. Bonfim ◽  
Jean-Hugues Dalle ◽  
Nimrod Buchbinder ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Research Funding ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Infectious Complications ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
History Of ◽  
Syncytial Virus

Background: Fanconi anemia (FA) is the most frequent genetic cause of bone marrow failure (BMF) due to a DNA repair mechanism defect. The natural history of FA is marked by progressive BMF during early childhood. Throughout life, the hematopoietic situation may change by clonal evolution toward myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure in FA patients. The role of HSCT for FA patients with AML or advanced MDS is less defined. Currently, HSCT first line result offers 50% Overall Survival (OS) for patients with cytogenetic abnormalities only and 30% OS for patients with advanced MDS or AML in FA (Ayas et al., JCO 2013; Mitchell et al., BJH 2014). We previously reported a FLAG-sequential approach in 6 patients with FA (5 AML and 1 advanced MDS), all alive at a median follow-up of 28 months (Talbot et al., Hematologica 2014). We update here those patients and report 12 more patients treated by FLAG-sequential since then. Materials & Methods: This retrospective study (2006-2019) was conducted in 7 centers in France and Brazil on behalf of the French Reference Center for Aplastic Anemia to evaluate FLAG-sequential in FA patients with morphological clonal evolution (no patients with cytogenetic abnormalities only). The study was conducted in accordance with the Declaration of Helsinki. Anonymous data collection was declared to the appropriate authorities. The FLAG-sequential treatment consisted of FLAG, Fludarabine 30 mg/m²/d for five days and Cytarabine 1 g/m²x2/d with G-CSF for five days, which was followed three weeks later by Cyclophosphamide 10 mg/kg/d for four days, Fludarabine 30 mg/m²/d for four days and TBI 2 Gy (Fig 1A). In a haploidentical setting, Cyclophosphamide at 30 mg/kg/d was performed only in post-transplantation, at Days +4 and +5 (Fig 1B). Results: Eighteen patients were included with 14 AML, 1 acute lymphoblastic leukemia (ALL), and 3 RAEB-2 (Table 1). The median age at the time of HSCT was 22 years (4-37 years). Fifteen patients (83%) were older than 10 years at the time of HSCT. The median follow-up was 31 months (3- 153 months). Eight patients (44%) had complex karyotype. None of the included patients had a history of solid malignancies before HSCT. All patients engrafted. The cumulative incidence of neutrophil engraftment at Day 60 was 94% (95% CI 63-100%) with a median of 18 days (12-343 days). The cumulative incidence of platelet engraftment at Day 60 was 83% (95% CI 50%-96%) with a median of 25 days (17-245 days). The donor chimerism was complete at Day +100 for 15 patients. The three patients without full donor chimerism at Day +100 either had a relapse (n=1) and 2 early deaths before Day+100 from steroid-refractory aGVHD (n=1) or septic shock (n=1). None of the patients received a second HSCT. Non-relapse mortality (NRM) at 3 years was 32% (95% CI 6-58%) (Fig 2). Cumulative incidence of grades II to IV aGVHD was 56% (35% grades III to IV). Cumulative incidence of extensive cGVHD was 16%. Infectious complications during HSCT include the following: CMV (n=8), EBV (n=2), adenovirus (n=4), BK virus (n=7), respiratory syncytial virus (n=1), candidaemias (n=2) and invasive aspergillosis (n=3). Progression free survival (PFS) and OS at 3 years were 53% (95%CI 32-89%) and 53% (95%CI 32-89%), respectively (Fig 2). Cumulative incidence of relapse at 3 years was 13% (95%CI 0-31%) (Fig 2). Seven patients died during the study. Causes of death were relapse (n=2), aGVHD (n=2), cGVHD (n=1), septic shock (n=1), and respiratory syncytial virus associated with invasive aspergillosis (n=1). GVHD-relapse free survival (GRFS) at 3 years was 48% (95%CI 29-78%). One patient had anal epidermoid carcinoma at 4 years after HSCT, which required multiple surgical ablations. Conclusion: With almost 3 years follow-up, which is long enough for our results to be considered robust, we report an OS and PFS of 53%, which compares favorably to historical controls since all of our 18 patients were treated with florid disease at time of HSCT (and not with cytogenetic abnormality only, known to be associated with a better prognosis). Toxicity is still a concern in this particular population of FA patients with notably a high rate of infectious complications. Future well designed prospective clinical trials will refine this sequential strategy, which appears promising in this particular difficult clinical situation. Disclosures Socie: Alexion: Consultancy. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

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.

Fanconi anemia type C–deficient hematopoietic stem/progenitor cells exhibit aberrant cell cycle control

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2081-2084 ◽  
Author(s):  
Xiaxin Li ◽  
P. Artur Plett ◽  
Yanzhu Yang ◽  
Ping Hong ◽  
Brian Freie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Progenitor Cells ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Cell Cycle Control ◽  
Cytokine Signaling ◽  
Compensatory Mechanism ◽  
Hematopoietic Stem ◽  
Type C

Abstract The pathogenesis of bone marrow failure in Fanconi anemia is poorly understood. Suggested mechanisms include enhanced apoptosis secondary to DNA damage and altered inhibitory cytokine signaling. Recent data determined that disrupted cell cycle control of hematopoietic stem and/or progenitor cells disrupts normal hematopoiesis with increased hematopoietic stem cell cycling resulting in diminished function and increased sensitivity to cell cycle–specific apoptotic stimuli. Here, we used Fanconi anemia complementation type C–deficient (Fancc–/–) mice to demonstrate that Fancc–/– phenotypically defined cell populations enriched for hematopoietic stem and progenitor cells exhibit increased cycling. In addition, we established that the defect in cell cycle regulation is not a compensatory mechanism from enhanced apoptosis occurring in vivo. Collectively, these data provide a previously unrecognized phenotype in Fancc–/– hematopoietic stem/progenitor cells, which may contribute to the progressive bone marrow failure in Fanconi anemia.

scholarly journals Holding All the Cards—How Fanconi Anemia Proteins Deal with Replication Stress and Preserve Genomic Stability

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 170 ◽  
Author(s):  
Arindam Datta ◽  
Robert M. Brosh Jr.
Keyword(s):  
Dna Damage ◽  
Fanconi Anemia ◽  
Excision Repair ◽  
Double Helix ◽  
Bone Marrow Failure ◽  
Molecular Genetic ◽  
Replication Stress ◽  
Gene Products ◽  
Hematopoietic Stem ◽  
Dna Double Helix

Fanconi anemia (FA) is a hereditary chromosomal instability disorder often displaying congenital abnormalities and characterized by a predisposition to progressive bone marrow failure (BMF) and cancer. Over the last 25 years since the discovery of the first linkage of genetic mutations to FA, its molecular genetic landscape has expanded tremendously as it became apparent that FA is a disease characterized by a defect in a specific DNA repair pathway responsible for the correction of covalent cross-links between the two complementary strands of the DNA double helix. This pathway has become increasingly complex, with the discovery of now over 20 FA-linked genes implicated in interstrand cross-link (ICL) repair. Moreover, gene products known to be involved in double-strand break (DSB) repair, mismatch repair (MMR), and nucleotide excision repair (NER) play roles in the ICL response and repair of associated DNA damage. While ICL repair is predominantly coupled with DNA replication, it also can occur in non-replicating cells. DNA damage accumulation and hematopoietic stem cell failure are thought to contribute to the increased inflammation and oxidative stress prevalent in FA. Adding to its confounding nature, certain FA gene products are also engaged in the response to replication stress, caused endogenously or by agents other than ICL-inducing drugs. In this review, we discuss the mechanistic aspects of the FA pathway and the molecular defects leading to elevated replication stress believed to underlie the cellular phenotypes and clinical features of FA.

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