Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 3872-3874 ◽  
Author(s):  
Holger Tönnies ◽  
Stefanie Huber ◽  
Jörn-Sven Kühl ◽  
Antje Gerlach ◽  
Wolfram Ebell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Risk Factor ◽  
Fanconi Anemia ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Molecular Cytogenetics ◽  
Complementation Group ◽  
Significant Survival ◽  
High Incidence ◽  
Marrow Cells

Abstract Fanconi anemia (FA) is a condition that induces susceptibility to bone marrow failure, myelodysplastic syndrome (MDS), and leukemia. We report on a high incidence of expanding clonal aberrations with partial trisomies and tetrasomies of chromosome 3q in bone marrow cells of 18 of 53 FA patients analyzed, detected by conventional and molecular cytogenetics. To determine the clinical relevance of these findings, we compared the cytogenetic data, the morphologic features of the bone marrow, and the clinical course of these patients with those of 35 FA patients without clonal aberrations of 3q. The 2 groups did not differ significantly with respect to age, sex, or complementation group. There was a significant survival advantage of patients without abnormalities of chromosome 3q. Even more pronounced was the risk assessment of patients with gains of 3q material with respect to the development of morphologic MDS and acute myeloid leukemia (AML). Thus, our data from 18 patients with 3q aberrations reveal that gains of 3q are strongly associated with a poor prognosis and represent an adverse risk factor in FA.

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 Preclinical correction of human Fanconi anemia complementation group A bone marrow cells using a safety-modified lentiviral vector

Gene Therapy ◽  
2010 ◽  
Vol 17 (10) ◽  
pp. 1244-1252 ◽  
Author(s):  
P S Becker ◽  
J A Taylor ◽  
G D Trobridge ◽  
X Zhao ◽  
B C Beard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Cells ◽  
Lentiviral Vector ◽  
Complementation Group ◽  
Group A ◽  
Marrow Cells

NKG2D-Mediated Marrow Injury in Paroxysmal Nocturnal Hemoglobinuria and Its Related Disorders.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3674-3674
Author(s):  
Nobuyoshi Hanaoka ◽  
Tatsuya Kawaguchi ◽  
Kentaro Horikawa ◽  
Shoichi Nagakura ◽  
Sonoko Ishihara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Cells ◽  
Close Association ◽  
Bone Marrow Failure ◽  
Γδ T Cells ◽  
Refractory Anemia ◽  
Nkg2d Ligands ◽  
Marrow Cells

Abstract Immune mechanism is considered to exert in the pathogenesis of marrow failure in paroxysmal nocturnal hemoglobinuria (PNH), idiopathic aplastic anemia (AA) and myelodysplastic syndromes (MDS); however, the molecular events are unknown. We have currently reported the appearance of NKG2D ligands such as cytomegalovirus glycoprotein UL16 binding proteins (ULBPs) and MHC class I-related chains A and B (MICA/B) on granulocytes and CD34+ marrow cells of some patients with PNH and its related diseases (Hanaoka N, et al. Blood. 2006;107:1184–1191). ULBP and MICA/B are stress-inducible membrane proteins that appear in infection and transformation. The ligands share NKG2D receptor on lymphocytes such as NK, CD8+ T, and γδ T-cells and promote activation of the lymphocytes. Cells expressing the ligands are then deadly injured by NKG2D+ lymphocytes (Groh, PNAS 1996; Cosman, Immunity 2001). Indeed, cells expressing NKG2D ligands were killed in vitro by autologous NKG2D+ lymphocytes of our patients (Hanaoka N, et al. Blood. 2005;106:304a; Blood. 2006;108:295a). In further analysis, ligands were detected on granulocytes in 47 (53%) of 88 patients: 11 (58%) of 19 PNH, 28 (60%) of 47 AA, and 8 (36%) of 22 refractory anemia. Ligands were also detected on immature bone marrow cells in all 11 patients (3 PNH, 5 AA, and 3 refractory anemia) who permitted analysis of their marrow cells. In the patients, it is conceivable that blood cells were exposed to a certain stress to induce NKG2D ligands, leading to NKG2D-mediated marrow injury. We also observed a close association of the ligand expression with pancytopenia and favorable response to immunosuppressive therapy by prospective analysis of 5 patients (3 AA-PNH syndrome and 2 AA) for more than one year up to 5 years. Thus, we here propose that NKG2D-mediated immunity, which drives both NK and T-cells, is critically implicated in the pathogenesis of bone marrow failure of PNH and its related disorders.

Bone Marrow Failure and Developmental Delay Caused By Mutations in Poly(A)-Specific Ribonuclease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2404-2404
Author(s):  
Santhosh Dhanraj ◽  
Sethu Madhava Rao Gunja ◽  
Adam P Deveau ◽  
Mikael Nissbeck ◽  
Boonchai Boonyawat ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mental Illness ◽  
Developmental Delay ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Biological Significance ◽  
Dyskeratosis Congenita ◽  
Ribosome Profile ◽  
Neurological Phenotype ◽  
Marrow Cells

Abstract Background: Deadenylation is a major mechanism that regulates RNA function and fate. Several mammalian deadenylases have been identified. Poly (A)-specific ribonuclease (PARN) is one of the major mammalian deadenylases that trims single-stranded poly (A) tails of mRNAs and oligoadenylated tails of H/ACA box snoRNAs and microRNAs. RNA biogenesis has emerged as a mechanism underlying several inherited diseases including well known inherited bone marrow failure syndromes (IBMFSs) such as Diamond Blackfan anemia, dyskeratosis congenita and Shwachman-Diamond syndrome. Little is known about the biological significance of germline mutations in PARN. Methods: Genome-wide screen for copy number alterations was used to identify causal mutations in patients with hematological and neurological manifestations. Four patients were identified with deletions in the PARN gene. Genomic, biochemical, cellular and knockdown experiments in human bone marrow cells and in zebrafish have been performed to clarify the role of PARN in the human disease. Results: We identified large monoallelic deletions in PARN in four patients with developmental delay or mental illness. One patient in particular had a severe neurological phenotype, central hypomyelination, and severe bone marrow failure. This patient had an additional missense mutation on the non-deleted allele and had severely reduced PARN protein and deadenylation activity. Clonogenic assays of the patient's bone marrow cells showed reduced potential to generate hematopoietic colony. Fibroblasts from the patient with biallelic mutations showed markedly slow growth. Large proportion of the cells accumulated in the G1/G0 phase of cell cycle, suggesting impaired transition from G1 to the S phase. Cells from this patient also had impaired oligoadenylation of specific H/ACA box snoRNAs and scaRNAs, including the telomerase RNA component (TERC). Importantly, PARN-deficient patient cells manifested abnormalities in two pathways that are affected in IBMFSs: short telomeres and an aberrant ribosome profile. This combination of abnormalities is seen in patients with severe variants of dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome). Knocking down PARN in human CD34+ marrow cells from healthy donors revealed marked defect in clonogenic potential. Morpholino knockdown of parn in zebrafish resulted in reduced formation of red blood cells and granulocytes. Conclusions: We report for the first time four patients from three different families with developmental delay or mental illness, who carried large monoallelic PARN deletions that have not been reported in healthy controls. This indicates that large PARN deletions in humans result in a neurological phenotype. Further, we showed that biallelic PARN mutations that results in markedly reduced protein, cause severe bone marrow failure and severe global central hypomyelination, similar to what is seen in patients with severe forms of dyskeratosis congenita. The identified defects suggest a new disease mechanism, in which PARN-deficiency disrupts the polyadenylated state of H/ACA box RNA molecules that in turn influences ribosome profile and telomere length and cause hematological and neurological defects. Disclosures No relevant conflicts of interest to declare.

scholarly journals In vivorepopulation ability of genetically corrected bone marrow cells from Fanconi anemia patients

2006 ◽  
Vol 103 (7) ◽  
pp. 2340-2345 ◽  
Author(s):  
Odile Cohen-Haguenauer ◽  
Bruno Péault ◽  
Cécile Bauche ◽  
Marie-Thérèse Daniel ◽  
Ibrahim Casal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Cells ◽  
Marrow Cells

scholarly journals Clinical severity in Fanconi anemia correlates with residual function of FANCB missense variants

2019 ◽  
Author(s):  
Moonjung Jung ◽  
Ramanagouda Ramanagoudr-Bhojappa ◽  
Sylvie van Twest ◽  
Rasim Ozgur Rosti ◽  
Vincent Murphy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Congenital Abnormalities ◽  
Bone Marrow Failure ◽  
Complementation Group ◽  
Clinical Severity ◽  
List Type ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Fancd2 Monoubiquitination

ABSTRACTFanconi anemia (FA) is the most common genetic cause of bone marrow failure, and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry (IFAR). Those with FANCB deletion or truncation demonstrate earlier than average onset of bone marrow failure, and more severe congenital abnormalities compared to a large series of FA individuals in the published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. For FANCB missense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization was associated with two missence variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays showed earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity is linked to the extent of residual FANCD2 monoubiquitination.KEY POINTSX-linked FANCB pathogenic variants predominantly cause acute, early onset bone marrow failure and severe congenital abnormalitiesBiochemical and cell-based assays with patient variants reveal functional properties of FANCB that associate with clinical severity

scholarly journals High incidence of B cell lymphomas derived from thymectomized AKR mice expressing TL.4 antigen.

1985 ◽  
Vol 162 (3) ◽  
pp. 1081-1086 ◽  
Author(s):  
A Peled ◽  
N Haran-Ghera
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cell ◽  
Bone Marrow Cells ◽  
B Cell Lymphomas ◽  
T Cell Lymphomas ◽  
High Incidence ◽  
Membrane Components ◽  
Akr Mice ◽  
Marrow Cells

AKR mice, 6-12 mo after birth, display a high incidence of spontaneous T cell lymphomas that can be prevented by thymus removal at the age of 1-3 mo. We report here the presence of dormant preleukemic cells among bone marrow cells of 8-12-mo-old AKR mice that have been thymectomized when 40-60 d old. Transplantation of bone marrow cells from these thymectomized AKR donors into syngeneic or hybrid (AKR X DBA/2)F1 intact or thymectomized recipients resulted in lymphoma development of AKR origin in 80-100% of the recipients. Analysis, by flow microfluorometry, of the antigenic cell surface phenotypes of the developing lymphomas revealed that all tumors were B cell lymphomas, since the cells stained with class-specific anti-IgM reagents and other reagents specific for B cells (RA3-2C2, RA3-6B2, anti-I-A, and anti-Fc receptor), and were Thy-1-. All these B cell tumors also expressed two T cell differentiation antigens, TL.4, found exclusively on T cell lymphomas, and Lyt-1 antigen, previously shown (11) to be expressed on some B cell neoplasms. The surface markers mu, I-A, RA3-2C2, and TL.4 identified by immunofluorescence, were shown to be integral membrane components synthesized by the tumor cells, rather than passively acquired proteins.

The Co-Recessive Inheritance Model: A Paradigm for Fanconi Anemia and Other Bone Marrow Failure Syndromes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3760-3760
Author(s):  
W. Clark Lambert ◽  
Monique M. Brown ◽  
Santiago A. Centurion
Keyword(s):  
Bone Marrow ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Normal Population ◽  
Bone Marrow Failure ◽  
Significant Proportion ◽  
Complementation Group ◽  
Recessive Model ◽  
Compound Heterozygous ◽  
Recessive Inheritance

Abstract One of us (WCL) has previously proposed a mathematical model, Co-Recessive Inheritance, for inherited diseases associated with DNA repair deficiencies (Lambert WC, Lambert MW: Mutat. Res., 1985;145:227–234; Lambert WC: Keynote Address, 21st Anniversary Celebration, MRC Cell Mutation Unit, University of Sussex, UK. Mutat. Res., 1992;273:179–102). The model is also applicable to diseases associated with defective cell cycle modulation following specific types of DNA damage, such as Fanconi Anemia, with or without additional defects in DNA repair. The model proposes that in some complementation groups of these diseases defective alleles at more than one locus are required for the disease phenotype to be expressed. It follows from the model (A readily understandable derivation will be presented.) that the carrier frequencies of the genes involved are very much higher than would be predicted based on classical population genetics. This may impact on recent observations of higher than expected co-inheritance of defective alleles of Fanconi Anemia and Bloom Syndrome genes along with BRCA genes in certain populations (e.g., Koren-Michowitz, M, et al.: Am. J. Hematol., 2005;78:203–206), and provides an explanation for the lower than expected incidence of cancer in these individuals. It also provides an explanation for finding biallelic defects in the same DNA repair genes in more than one complementation group of Fanconi Anemia (Howlett NG, et al.: Science, 2002;297:606–609). The Co-Recessive Model predicts that other findings of this nature are to be expected, and provides some guidelines that may be helpful in the process of gene discovery in Fanconi Anemia. Among the more important of these are 1) that the search for defective genes in each complementation group should not cease when one such gene is found, even if one or more patients in the group is homozygous or compound heterozygous for defective alleles of that gene, and 2) that carrier frequencies for some Fanconi Anemia genes may be much higher than would otherwise be anticipated, with a significant proportion of the normal population being carriers. If the latter hypothesis is correct, it follows that the relevance of these rare diseases and their associated genes to disease, including bone marrow failure, in the general population is dramatically greater than has been generally believed.

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

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5140-5148 ◽  
Author(s):  
Qing-Shuo Zhang ◽  
Laura Marquez-Loza ◽  
Laura Eaton ◽  
Andrew W. Duncan ◽  
Devorah C. Goldman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Abnormal Cell ◽  
Colony Forming Capacity ◽  
Cell Cycle Status ◽  
Cell Repopulation ◽  
Supportive Function

Abstract 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.

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