Dyskeratosis Congenita: Evaluation of Immune Status and Hematopoietic Stem Cell Transplantation. A Literature and EBMT Data Base Survey of 75 Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4144-4144
Author(s):  
Elisabeth T Korthof ◽  
Judith Van der Zalm ◽  
Martine F Raphael ◽  
Dorine Bresters ◽  
Jakub Tolar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Immune Status ◽  
Bone Marrow Failure ◽  
Chronic Gvhd ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Immune Defect ◽  
Reduced Intensity

Abstract Abstract 4144 Dyskeratosis congenita (DC) is a rare inherited disease characterized by mucocutaneous abnormalities, progressive hematopoietic bone marrow failure as well as a predisposition to pulmonary fibrosis and malignancies. Unknown is if the lymphocytic lineage is affected as well. DC is a disease of defective telomere maintenance; the known mutations are located in the telomere biology genes DKC1, TERC, TERT, TINF2, NHP2 and NOP10 with X-linked, autosomal dominant and recessive inheritance patterns. Allogeneic stem cell transplantation (SCT) is the only potential curative treatment for bone marrow failure in patients with classical DC; however available data on SCT is scarce. Our objectives in this retrospective literature and database study on classical DC were to evaluate immune status at diagnosis, transplant procedures performed, engraftment, complications and survival. Data from all accessible English, French, German and Dutch articles of PubMed, UptoDate, EMBASE and Cochrane presenting classical DC patients with SCT were collected in a DC specific database. Corresponding authors were asked for additional data and for registration at the European Blood and Marrow Transplantation group (EBMT) database to prevent double inclusion. Forty-seven patients were found this way. From the EBMT Working Parties Inborn Errors and Severe Aplastic Anemia data bases we included 28 patients. In total 75 patients with DC who underwent 83 SCTs (8 patients were grafted twice) were included. Immune status at diagnosis could be studied in 26 patients, comparing data to age-matched controls. One or more decreased lymphocyte subset counts (CD3, CD4, CD8, NK or B cells) were found in 9/13 evaluable patients (69%) while IgG, IgM and IgA values were normal in 16/22 evaluable patients (73%). For the whole group, data on gene mutations were only available for 6 patients; data on 13 cases are pending. Median age at SCT was 11.1 (1.0–28.8) years. Most donors were matched siblings, matched unrelated or mismatched unrelated (n=32, 20, and 10, resp.). Stem cell source was BM in 56, PB in 7 and CB in 9 cases (unknown, 3). Conditioning was myeloablative in 30, reduced intensity (RIC) in 32 and unknown in 13 cases without difference in engraftment and chimaerism but with a tendency towards less TRM and better survival in RIC. Acute graft-versus-host-disease (GvHD) grade II-IV was seen in 13/54 evaluable cases, chronic GvHD in 13/50 evaluable cases. Cyclosporine monotherapy was associated with an OR of 5.5 (CI 1.073–28.198) for chronic GvHD when compared to cyclosporine combination therapy. Alive at last follow-up were 34/75 patients; causes of death in 11/26 evaluable patients were transplant related in 6/11 and DC related in 5/11. Probability of survival was 66% at 5 years and 28% at 10 years post SCT. Pulmonary fibrosis was diagnosed in 6/75 cases; malignancies in 3/41 evaluable cases. This is the largest study ever conducted on immune status and SCT in DC suggesting an immune defect inherent to DC and a superiority for reduced intensity conditioning. DC related complications are the main cause of death later than 5 years after SCT, underlining the need for prolonged follow-up after SCT. At this moment we are adding data of another 8 patients from the Eastern Mediterranean Bone Marrow Transplant group. Continuing international collaboration is vital to understand the immune defect which could be primary related to the genotype or secondary to general attrition of rapidly dividing cells with inefficient telomere maintenance, and find ways to improve transplant procedures in this rare disease, classical DC. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Revesz syndrome revisited

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Michael Karremann ◽  
Eva Neumaier-Probst ◽  
Frank Schlichtenbrede ◽  
Fabian Beier ◽  
Tim H. Brümmendorf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
English Literature ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Kaplan Meier ◽  
Low Prevalence

Abstract Background Revesz syndrome (RS) is an extremely rare variant of dyskeratosis congenita (DKC) with only anecdotal reports in the literature. Methods To further characterize the typical features and natural course of the disease, we screened the English literature and summarized the clinical and epidemiological features of previously published RS cases. In addition, we herein describe the first recorded patient in central Europe. Results The literature review included 18 children. Clinical features are summarized, indicating a low prevalence of the classical DKC triad. All patients experienced early bone marrow failure, in most cases within the second year of life (median age 1.5 years; 95% CI 1.4–1.6). Retinopathy occurred typically between 6 and 18 months of age (median age 1.1 years; 95% CI 0.7–1.5). The incidence of seizures was low and was present in an estimated 20% of patients. The onset of seizures was exclusively during early childhood. The Kaplan–Meier estimate of survival was dismal (median survival 6.5 years; 95% CI 3.6–9.4), and none of the patients survived beyond the age of 12 years. Stem cell transplantation (SCT) was performed in eight children, and after a median of 22 months from SCT four of these patients were alive at the last follow up visit. Conclusion RS is a severe variant of DKC with early bone marrow failure and retinopathy in all patients. Survival is dismal, but stem cell transplantation may be performed successfully and might improve prognosis in the future.

DNA Damage Accumulation, Accelerated Hematopoietic Stem Cell Aging, and Partial Reversal by Antioxidant Treatment in a Mouse Model of Dyskeratosis Congenita.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 498-498
Author(s):  
Baiwei Gu ◽  
JianMeng Fan ◽  
Monica Bessler ◽  
Philip Mason
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cell Function ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Cell Aging ◽  
Female Mice ◽  
Stem Cell Aging ◽  
Population Doublings

Abstract Abstract 498 X-linked dyskeratosis congenita (DC) caused by mutations in DKC1, encoding the protein dyskerin, is the most common form of DC, a severe inherited bone marrow failure (BMF) syndrome associated with a predisposition to malignancy. Dyskerin is a component of small nucleolar ribonucleoprotein particles(snoRNPs) that modify specific residues in nascent ribosomal RNA(rRNA) molecules and also forms part of the telomerase complex responsible for synthesizing the telomere repeats at the ends of chromosomes. Strong evidence suggests that compromised telomerase function is the major cause of DC but defects in ribosome biogenesis may contribute to the disease. Excessive telomere shortening resulting in premature cellular senescence is thought to be the primary cause of bone marrow failure in dyskeratosis congenita. Our previous data showed that, in mice, cells expressing a Dkc1 mutation (Dkc1Δ15) had a telomerase dependent but telomere length independent growth defect. Here we show that the growth rate of Δ15 MEF cells was lower when cultured at both ambient oxygen (21%) and low (3%) oxygen. In 21% oxygen both Δ15 and WT cells stopped growing and entered senescence after 8-10 population doublings, with the Δ15 cells growing more slowly than the WT cells. In 3% oxygen Δ15 cells grew more slowly and entered senescence earlier than WT cells. Further investigations reveal that both γ-H2AX foci number and reactive oxygen species (ROS) levels in Δ15 cells were significantly higher than in WT cells with increased passage number even when cultured in low oxygen. Increased levels of γ-H2AX and p53 in Dkc1Δ15 mice, particularly in older mice, were also detected in liver, spleen and bone marrow. To study the effect of the mutation on stem cell function during aging, we carried out competitive repopulation experiments using the CD45.1/CD45.2 congenic system. Irradiated mice were injected with a 1:1 mixture of Dkc1Δ15 and Dkc1+ bone marrow from old (77-88w) or young (10w) animals. Old Dkc1Δ15cells are less able to compete with age matched WT cells in primary recipients, making up only 20% of cells after 12 weeks compared with 40% for the young cells. Moreover, serial transplantation results show that, in secondary recipients, BM cells from old Dkc1Δ15 mice were not detectable while Dkc1Δ15 cells from young mice still comprise 10-30% of the bone marrow after 12 weeks. These results strongly indicate the Dkc1Δ15 mutation causes decay of stem cell function with age. Because of the association with ROS we asked whether treatment with an antioxidant could rescue the growth disadvantage of Δ15 cells. We grew primary MEF cells from Dkc1Δ15/+ female mice in the presence or absence of 100 M N-acetyl cysteine (NAC), a clinically approved antioxidant. These cultures consist in early passages of 50% cells expressing WT and 50% expressing Δ15 dyskerin, reflecting random X-chromosome inactivation, Without NAC the WT cells almost completely outgrew the Δ15 cells after 11 population doublings but in the presence of NAC the Δ15 cells are still clearly present after 15 population doublings, suggesting that NAC at least partially rescues the growth disadvantage of dyskerin mutant cells. More impressively, the growth disadvantage of the Δ15 cells is also rescued in vivo in Dkc1Δ15/+ female mice given the NAC (1mg/ml) in their drinking water. Although the precise mechanism will be the subject of further investigation, these results point to a functional link between increased oxidative stress, defective telomere maintenance and stem cell aging in the pathogenesis of BMF in dyskeratosis congenita. Disclosures: Bessler: Alexion: Membership on an entity's Board of Directors or advisory committees.

Antioxidant Treatment Rescues An Accelerated Aging Phenotype In Dyskerin Mutated Bone Marrow Stem Cells.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2614-2614
Author(s):  
Baiwei Gu ◽  
Jian-meng Fan ◽  
Monica Bessler ◽  
Philip J Mason
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Cell Function ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Untreated Group ◽  
Telomere Maintenance ◽  
Antioxidant Treatment ◽  
Transplantation Experiments

Abstract Abstract 2614 X-linked Dyskeratosis Congenita (DC) is due to mutations in the DKC1 gene, which encodes the protein dyskerin. Dyskerin is a highly conserved nucleolar protein that, as part of a specialized nucleolar RNP, catalyzes the pseudouridylation of specific residues in newly synthesized ribosomal RNAs and spliceosomal snRNAs. Dyskerin also associates with telomerase and is involved in telomere maintenance. In addition to the well known effect of telomere homeostasis on cancer, it is evident that telomere maintenance may also be important in replicative aging because of telomere shortening due to the limited expression of telomerase activity in dividing somatic cells. Accumulating evidence suggests that dysfunctional telomeres resulting in premature cellular senescence is the primary cause of bone marrow failure in dyskeratosis congenita. It is important to determine the mechanism whereby Dkc1 mutations lead to premature cellular senescence in bone marrow. We have produced a line of mice containing a mutation, Dkc1Δ15, which is a copy of a pathogenic human mutation. Male Dkc1Δ15 mice showed a decrease in the proportion of B and T lymphocytes in peripheral blood and reduced body weight with age but no overt bone marrow failure syndrome phenotypes. Our previous competitive bone marrow transplantation experiments showed that the Dkc1Δ15 mutation caused decay of stem cell function with age. Bone marrow from older Dkc1Δ15 mice was markedly inefficient in repopulation studies compared with bone marrow from age matched wild type mice. We also found that N-acetyl cysteine (NAC) could at least partially rescue the growth disadvantage of dyskerin mutant spleen cells or fibroblasts which was associated with accumulation of DNA damage and reactive oxygen species. To determine if NAC, or other antioxidants might be useful therapeutically it is important to determine their effects on stem cell function, which is defective in DC. To this end we established a cohort of mice that were given NAC in their drinking water (1mg/ml) from 3-weeks of age and maintained on NAC for 1 year. We found that long term NAC treatment did not show significant side effects on the mice. They had slightly increased neutrophils, but no difference in life span and body weight compared with the untreated group. Impressively, old male Dkc1Δ15 mice showed corrected B and T cell proportions in peripheral blood after treatment with NAC. Competitive bone marrow transplantation experiments were carried out in which a 1:1 mixture of BM cells from mutant and WT mice was used to repopulated lethally irradiated recipient mice. These experiments showed that, when taken from NAC treated animals, old Dkc1Δ15 BM cells could compete with age matched WT cells with 40–45% of Dkc1Δ15 cells in primary recipients compared with only 20% for the untreated group. Moreover, after secondary transplantation, cells from the NAC treated group still represent 15–20% of Dkc1Δ15 cells in recipients while those from the untreated group could not be detected. These results strongly suggest that NAC treatment can partially restore the bone marrow repopulating ability of Dkc1Δ15 stem cells. Together with our previous results these data suggest that a pathogenic Dkc1 mutation, through its effect on telomerase, initiates stem cell aging before telomeres are short and that increased oxidative stress might play a role in this process. Moreover the effects of the mutation may be prevented or delayed by antioxidant treatment, although the precise mechanism will be the subject of future investigation. Disclosures: Bessler: Alexion Pharmaceutical Inc: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy.

Hematopoietic Stem Cell Transplantation following Reduced Intensity Conditioning for High Risk Patients with Paroxysmal Nocturnal Hemoglobinuria

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4407-4407
Author(s):  
Agata Mikolajewska ◽  
Haifa Kathrin Al-Ali ◽  
Nadezda Basara ◽  
Elliot Epner ◽  
Ernst Holler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity

Abstract Objectives: Paroxysmal nocturnal hemoglobinuria (PNH) is a non malignant acquired hematopoietic stem cell disorder that can cause severe complications such as arterial or venous thrombosis or deficient haematopoiesis. These patients have a high mortality rate and should be evaluated for allogeneic stem cell transplantation (SCT). However, conventional conditioning has been associated with high treatment related toxicity. We report here the extended follow up of 7 previously published and 4 additional patients with high risk PNH after allogeneic HCT with reduced intensity conditioning (RIC). Patients: Eleven patients (3 males) with a median time from diagnosis to SCT of 16 (range 4 to 59) months were treated with red blood cell transfusions (n=9), anticoagulation (n=3), or immunosuppression (n=10): cyclosporine A (CSA, n=3), azathioprin (n=1), mycofenolate mofetil (MMF, n=1), antithymocyte globulin (n=1) or systemic steroids (n=9) until SCT. High risk PNH was characterized by venous thromboses: sinus veins (n=1), liver veins (n=3), vena portae (n=1), mesenterial veins (n=1) or thrombosis of lower extremity (n=1); bone marrow failure (n=6); recurrent life threatening haemolysis (n=8) or infections (n=5). Seven patients had more than one high risk feature. The median age at SCT was 34 (range 22 to 49) years. Conditioning regimen consisted of 2 Gy total body irradiation (TBI) at day 0 and fludarabine (30 mg/m2) at day-4 to -2 followed by treatment with MMF and CSA. The stem cell donors were related (n=2), allele matched unrelated (n=7) or mismatched (n=2). Results: The median follow up was 43 (range 2–101) months after SCT. The median time until neutrophil recovery was 17 (range 0–29) days and 4/11 patients (36%) did not develop ANC<500/l. All but one patient (91%) showed primary donor engraftment with a median T-cell chimerism of 59 (range 38.3–99.3) % in the bone marrow at day 28 after SCT. The patient with primary graft failure received a second transplant from an alternative donor after RIC with 3 Gy TBI and showed stable engraftment. Six out of 11 (55%) patients developed grade II or III acute graft-versus-host disease (GvHD), which was treated with systemic steroids in 5 patients. Extensive chronic GvHD occurred in 3/11 (27%) of the patients. Three patients (27%) died of complications (pancreatitis with subsequent multiorgan failure, pseudomonas sepsis and haemorrhage) following steroid treatment for acute (n=1) and extensive (n=2) chronic GvHD 2, 12.5 and 14 months after SCT. The remaining 8 patients are alive and without clinical and laboratory evidence of PNH after a median follow up 61.5 (range 10–101) months after SCT. All surviving patients show an ECOG of 0–1 and 4/8 patients (50%) are off all immunsuppression. Conclusions: Allogeneic HCT with reduced intensity conditioning induces durable eradication of the PNH clone. The treatment related mortality even in high risk PNH with severe organ dysfunction was acceptable and due to complications after GVHD. All long term survivors have a good performance status and half of them are without any immunosuppression.

Outcome of Busulfan and Fludarabine-Based Reduced Intensity Conditioning Regimen for Related and Unrelated HSCT in Fanconi Anemia Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1964-1964
Author(s):  
Saba Azarnoush ◽  
Raphael Porcher ◽  
Regis Peffault de la Tour ◽  
Karima Yakouben ◽  
Benedicte Bruno ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Dose ◽  
Acute Gvhd ◽  
Bone Marrow Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Secondary Malignancy ◽  
Secondary Malignancies ◽  
Reduced Intensity

Abstract Abstract 1964 Rationale: HSCT is the only curative treatment for Fanconi Anemia (FA) pts with either bone marrow failure or MDS/Leukemia. Due to characteristic chromosomal instability, the poor outcome of FA pts transplanted after so-called conventional myelo-ablative conditioning regimen has been proved. Then, reduced-intensity conditionning regimen (RIC) has been considered for years as a model for allogeneic HSCT in FA pts. The use of fludarabine-based cond' regimen from about 2000 increased dramatically the overall survival of FA pts. Different Flu-based RIC were developed. Patients and method: Between Feb'02 and Dec'10, 17 FA pts from 3 academic French centers were included: 11 from R. Debre hospital, 5 from St Louis hospital and 1 from J. de Flandre hospital. All pts underwent HSCT because of bone marrow failure. They presented no MDS or leukemia. All time-to-event outcomes were counted from the date of HSCT to the date of event or date of last follow-up, except acute GVHD that was arbitrarily censored at 200 days. Death was considered as a competing risk in analyses of neutrophil and platelet recovery and chronic and acute GVHD. Overall survival was estimated using Kaplan-Meier product-limit estimator. For competing risks analyses, cumulative incidences were estimated using usual methodology. Results: Median age at diagnosis and at HSCT were 4.7 years (range 1,8-9,3) and 7,4 years (range 4,4-15,2), respectively. 12 pts presented with less than 3 FA-related malformations and 5 with more than 3 malformations. 2 patients received more than 20 transfusions before HSCT, whereas 8 pts received less than 20 transfusions and 7 patients did not received any. 2 patients received androgen therapy before HSCT. All patients received the same RIC i.e. fludarabine 30mg/m2/d × 3d, cyclophosphamide 10mg/kg/d × 4d and IV busulfan (Bu) 0.75 of body weight- adjusted recommended dose (equivalent to 6.4mg/kg total dose of oral Bu). This RIC did not contain any irradiation. Graft versus-host disease (GvHD) prophylaxis consisted of CSA associated with MMF or corticosteroids. Donors were either matched related (sibling, n= 6; other, n=2) or unrelated (10/10, n= 6; 9/10, n= 3). Stem cell sources were BM (n=10), UCB (n=4) and PBSC (n=2). 9 out of 17 pts had a donor from the same gender whereas 4 male recipients received transplant from female donor. CMV status were −/−, −/+, +/− and +/+ for 8, 4, 1 and 4 D/R pairs, respectively. Median follow-up was 32 months (range 3–102). Successful engraftment was obtained in all patients with a median time for neutrophil recovery of 17 days (range 10–42). All patients presented with 100% donor chimerism. One patient experimented secondary graft failure and died at D291 from infection and renal failure. During transplant procedure, 13 pts experimented at least one severe infectious complication (staphylococcus n=2; pseudomonas n=1; aspergillus n= 2; candida n=2; viral reactivation n= 13). 1 pt presented with moderate hepatic veno-occlusive disease. Five pts died from TRM and 12 pts remained alive in a good health condition. 36 month OS was 69% (95%CI 50 to 96). Cumulative incidence of grade 2 to 4 acute GVHD was 71% (95%CI: 41–87). 5 pts presented with either limited (n=4) or extensive (n=1) chronic GvHD and 36 month cumulative incidence of chronic GVHD was 33% (95%CI 11 to 58). To date, no pt had secondary malignancy. Discussion: Our study confirms the good results obtained by other groups when using flu-based RIC in FA pts. Indeed, satisfying engraftment and long-time survival rates were obtained without any TBI, irrespective of the stem cell source and the donor type. However, we have a concern regarding the cGVHD rate we obtained. As demonstrated by an on-going study of EBMT registry, the risk of secondary malignancy in these pts is statistically correlated to cGvHD. Then, this rate still remains probably too high in our study, even though only one pt presented with extensive cGvHD and no pts developed any secondary malignancy. But this could be explained by the short follow-up. Suppression of one alkalyting agent may reduce both cGVHD incidence and other tissue injuries leading to secondary malignancies. Then, we claim for suppression of Bu for related donor HSCT. In FA pts receiving transplant from unrelated donor, the relative impact of either low-dose IV-Bu – as we used here - or low-dose irradiation on toxicity and especially development of secondary malignancies remains to be evaluated. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A zebrafish model of dyskeratosis congenita reveals hematopoietic stem cell formation failure resulting from ribosomal protein-mediated p53 stabilization

Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5458-5465 ◽  
Author(s):  
Tamara C. Pereboom ◽  
Linda J. van Weele ◽  
Albert Bondt ◽  
Alyson W. MacInnes
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Ribosomal Proteins ◽  
Bone Marrow Failure ◽  
Ribosomal Subunit ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Zebrafish Model ◽  
Hematopoietic Stem

Abstract Dyskeratosis congenita (DC) is a bone marrow failure disorder characterized by shortened telomeres, defective stem cell maintenance, and highly heterogeneous phenotypes affecting predominantly tissues that require high rates of turnover. Here we present a mutant zebrafish line with decreased expression of nop10, one of the known H/ACA RNP complex genes with mutations linked to DC. We demonstrate that this nop10 loss results in 18S rRNA processing defects and collapse of the small ribosomal subunit, coupled to stabilization of the p53 tumor suppressor protein through small ribosomal proteins binding to Mdm2. These mutants also display a hematopoietic stem cell deficiency that is reversible on loss of p53 function. However, we detect no changes in telomere length in nop10 mutants. Our data support a model of DC whereupon in early development mutations involved in the H/ACA complex contribute to bone marrow failure through p53 deregulation and loss of initial stem cell numbers while their role in telomere maintenance does not contribute to DC until later in life.

scholarly journals Effect of stem cell factor on in vitro erythropoiesis in patients with bone marrow failure syndromes

Blood ◽  
1992 ◽  
Vol 80 (12) ◽  
pp. 3000-3008
Author(s):  
BP Alter ◽  
ME Knobloch ◽  
L He ◽  
AP Gillio ◽  
RJ O'Reilly ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Mononuclear Cells ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Normal Numbers ◽  
Erythroid Progenitors ◽  
Bone Marrow Failure Syndromes

Stem cell factor (SCF) enhances normal hematopoiesis. We examined its effect in vitro on bone marrow and blood progenitors from patients with inherited bone marrow failure syndromes, including 17 patients each with Diamond-Blackfan anemia (DBA) and Fanconi's anemia (FA), 3 with dyskeratosis congenita (DC), and 1 each with amegakaryocytic thrombocytopenia (amega) and transient erythroblastopenia of childhood (TEC). Mononuclear cells were cultured with erythropoietin (Ep) alone or combined with SCF or other factors. SCF increased the growth of erythroid progenitors in cultures from 50% of normal controls, 90% of DBA, 70% of FA, 30% of DC, and the amega and TEC patients; normal numbers were reached in 25% of DBA studies. Improved in vitro erythropoiesis with SCF in all types of inherited marrow failure syndromes does not suggest a common defect involving kit or SCF, but implies that SCF may be helpful in the treatment of hematopoietic defects of varied etiologies.

scholarly journals Effect of stem cell factor on in vitro erythropoiesis in patients with bone marrow failure syndromes

Blood ◽  
1992 ◽  
Vol 80 (12) ◽  
pp. 3000-3008 ◽  
Author(s):  
BP Alter ◽  
ME Knobloch ◽  
L He ◽  
AP Gillio ◽  
RJ O'Reilly ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Mononuclear Cells ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Normal Numbers ◽  
Erythroid Progenitors ◽  
Bone Marrow Failure Syndromes

Abstract Stem cell factor (SCF) enhances normal hematopoiesis. We examined its effect in vitro on bone marrow and blood progenitors from patients with inherited bone marrow failure syndromes, including 17 patients each with Diamond-Blackfan anemia (DBA) and Fanconi's anemia (FA), 3 with dyskeratosis congenita (DC), and 1 each with amegakaryocytic thrombocytopenia (amega) and transient erythroblastopenia of childhood (TEC). Mononuclear cells were cultured with erythropoietin (Ep) alone or combined with SCF or other factors. SCF increased the growth of erythroid progenitors in cultures from 50% of normal controls, 90% of DBA, 70% of FA, 30% of DC, and the amega and TEC patients; normal numbers were reached in 25% of DBA studies. Improved in vitro erythropoiesis with SCF in all types of inherited marrow failure syndromes does not suggest a common defect involving kit or SCF, but implies that SCF may be helpful in the treatment of hematopoietic defects of varied etiologies.

Genome Wide Linkage Analysis Suggests Genetic Heterogeneity in Autosomal Recessive Dyskeratosis Congenita, with One Locus on Chromosome 15.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1054-1054
Author(s):  
Amanda Walne ◽  
Tom Vulliamy ◽  
Anna Marrone ◽  
Inderjeet Dokal
Keyword(s):  
Bone Marrow ◽  
Linkage Analysis ◽  
Genetic Heterogeneity ◽  
Autosomal Recessive ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Chromosome 15 ◽  
Lod Score ◽  
Genome Wide

Abstract Dyskeratosis congenita (DC) is a severe inherited premature aging syndrome characterised by muco-cutaneous abnormalities, bone marrow failure and an increased predisposition to cancer. X-linked recessive, autosomal dominant (AD) and autosomal recessive (AR) forms of the disease are recognised. Mutations in DKC1 and TERC have been identified in X-linked recessive and AD-DC, respectively. The products encoded by both of these genes are key components of the telomerase complex, which is responsible for maintaining telomere length after cell division. This has led to the suggestion that DC is primarily a disease of defective telomere maintenance. The international dyskeratosis congenita registry (Hammersmith Hospital, London) has information on 244 families with DC. Of these 30% have mutations in DKC1 and 6% have mutations in TERC. Disease causing mutations in the remaining 64% of patients have yet to be characterised. In an attempt to identify a candidate locus through homozygosity mapping, we performed a genome-wide scan using a maximum of 475 microsatellite markers (LMS-MD 10/5 ABI PRISM) on DNA from 19 affected individuals from 13 families with consanguineous marriage. No single marker was found to be homozygous in all individuals, although not all markers were typed in all individuals. 19% of markers were homozygous in four or more families across the chromosomes, but this dropped to 4% when the number of families that were homozygous was increased to six. Only six markers (1% approx.) were homozygous in seven or more families. This suggests there is considerable genetic heterogeneity amongst the AR-DC subset. To investigate this further we selected one family that showed a recessive pattern of inheritance with samples available from three affected individuals, three unaffected siblings and parents. Affected members in this family had the classical DC features of nail dystrophy, abnormal skin pigmentation, abnormal dentition and severe bone marrow failure in the index case. To try to identify a disease locus in this family, we typed the whole family at the markers where the affected individuals shared common homozygosity and analysed the data using Genehunter, a multi-point linkage analysis program, to obtain a LOD score (log10 of the odd ratio in favour of linkage). The maximum LOD score obtained for this family was 2.7 on chromosome 15, suggesting that a disease-causing locus is at chromosome 15q14. This particular location seems to be unique to this family as there is no overlap in homozygosity with any other family studied. It remains to be established how many loci there are, and whether a single gene causes DC in many of the AR families, or if each gene identified causes the disease in a small subset of families. In conclusion this work highlights the extent of genetic heterogeneity that exists in DC, with AR-DC being a very heterogeneous subtype which may involve several genes, but the locus of one AR-DC gene has been assigned to chromosome 15q14.

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