Aplastic Anaemia
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Anaplastic Anemia is not a cancer. AA is a rare disease in which the bone marrow is unable to produce adequate blood cells; leading to pancytopenia (deficiency of all types of blood cells). AA may occur at any age, but there is a peak in adolescence / early adulthood, and again in old age. Slightly more males than females are diagnosed with AA, also the disease is more common in the Far East. Patients successfully treated for aplastic anemia have a higher risk of developing other diseases later in life, including cancer.

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Fanconi Anaemia

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Information for Health Professionals / Researchers (4 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Kanda Y, Oshima K, Kako S, et al.
In vivo T-cell depletion with alemtuzumab in allogeneic hematopoietic stem cell transplantation: Combined results of two studies on aplastic anemia and HLA-mismatched haploidentical transplantation.
Am J Hematol. 2013; 88(4):294-300 [PubMed]
We evaluated the efficacy of in vivo T-cell depletion with alemtuzumab in two prospective studies according to the International Conference on Harmonisation (ICH)-Good Clinical Practice (ICH-GCP) guidelines; one was for patients with aplastic anemia (AA study) and the other was for patients who were undergoing hematopoietic stem cell transplantation (HSCT) from a 2- or 3-antigen-mismatched haploidentical donor (MM study). The final dose of alemtuzumab in these studies was 0.16 mg/kg/day for 6 days. At this dose, all of the 12 and 11 patients in the AA and MM studies, respectively, achieved initial engraftment and the incidences of Grade II-IV acute graft-versus-host disease (GVHD) were 0% and 18%. While cytomegalovirus (CMV) frequently reactivated, none of the patients developed fatal CMV disease. Transplantation-related mortality within 1 year after HSCT was observed in only two and one patients, respectively. The numbers of CD4+ and CD8+ T-cells and T-cell receptor rearrangement excision circles remained low within 1 year after HSCT. These findings suggest that the use of alemtuzumab at this dose in a conditioning regimen enables safe allogeneic HSCT even from a 2- or 3-antigen-mismatched donor. However, the use of a lower dose of alemtuzumab should be explored in future studies to accelerate immune recovery after HSCT.


Yao CJ, Du W, Zhang Q, et al.
Fanconi anemia pathway--the way of DNA interstrand cross-link repair.
Pharmazie. 2013; 68(1):5-11 [PubMed]
The study of rare genetic diseases usually inspires the research of cancer biology. Fanconi anemia (FA), is a rare cancer susceptibility syndrome with an incidence of only 1 per 350,000 births. FA is an autosomal recessive disease with three main features: chromosome instability, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), cisplatin and so on, and susceptible to a number of cancer types, mainly leukemia and squamous cell carcinomas of the head and neck or gynecologic system. DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking. However, FA pathway is closely linked with carcinogenesis and tumor drug resistance. This paper mainly focuses on the FA pathway and its progress in cancer research.


de Masson A, Bouaziz JD, Peffault de Latour R, et al.
Severe aplastic anemia associated with eosinophilic fasciitis: report of 4 cases and review of the literature.
Medicine (Baltimore). 2013; 92(2):69-81 [PubMed]
Diffuse eosinophilic fasciitis (Shulman disease) is a rare sclerodermiform syndrome that, in most cases, resolves spontaneously or after corticosteroid therapy. It has been associated with hematologic disorders, such as aplastic anemia. The clinical features and long-term outcomes of patients with eosinophilic fasciitis and associated aplastic anemia have been poorly described. We report the cases of 4 patients with eosinophilic fasciitis and associated severe aplastic anemia. For 3 of these patients, aplastic anemia was refractory to conventional immunosuppressive therapy with antithymocyte globulin and cyclosporine. One of the patients received rituximab as a second-line therapy with significant efficacy for both the skin and hematologic symptoms. To our knowledge, this report is the first to describe rituximab used to treat eosinophilic fasciitis with associated aplastic anemia. In a literature review, we identified 19 additional cases of eosinophilic fasciitis and aplastic anemia. Compared to patients with isolated eosinophilic fasciitis, patients with eosinophilic fasciitis and associated aplastic anemia were more likely to be men (70%) and older (mean age, 56 yr; range, 18-71 yr). Corticosteroid-containing regimens improved skin symptoms in 5 (42%) of 12 cases but were ineffective in the treatment of associated aplastic anemia in all but 1 case. Aplastic anemia was profound in 13 cases (57%) and was the cause of death in 8 cases (35%). Only 5 patients (22%) achieved long-term remission (allogeneic hematopoietic stem cell transplantation: n = 2; cyclosporine-containing regimen: n = 2; high-dose corticosteroid-based regimen: n = 1).


Tang X, Liu F, Li L, et al.
Antithymocyte globulin/antilymphocyte globulin plus kidney-nourishing Chinese medicinal: effect on severe aplastic anemia.
J Tradit Chin Med. 2012; 32(4):604-8 [PubMed]
OBJECTIVE: To explore the effect of antithymocyte globulin (ATG)/antilymphocyte globulin (ALG) plus kidney-nourishing Chinese medicinal (KNCM) on severe aplastic anemia (SAA).
METHODS: Twenty-five subjects of severe aplastic anemia were treated with ATG/ALD plus KNCM between 1992 and 2009, and the clinical data before and after treatment were collected and analyzed.
RESULTS: Of the 25 patients, 9 were nearly cured, 6 were improved, 5 were in remission, and 5 failed. The overall effective rate was 80.0%. The 3-year, 5-year, 10-year, 15-year survival rate were respectively 98.6%, 97.3%, 97.3%, 67.5%, and median survival time was 180 months. Compared to the conditions before administering the medication of ATG/ ALG plus KNCM, after 2 weeks, reticulocyte was first improved (P = 0.001); one month later, followed by palette (P = 0.037); two months later, by neutrophil cell in peripheral blood (P = 0.001); three months later, then by the hemoglobin (P = 0.012). By conducting 1-year follow-up, 1 case of complication--paroxysmal nocturnal hemoglobinuria (PNH) was identified and the patient still alive today.
CONCLUSION: ATG/ALG plus KNCM had better effect on SAA and could improve patients' survival rate.


Ye B, Chen D, Wu D, et al.
Effect of kidney-reinforcing, blood-activating and stasis-removing recipes on adhesion molecule expression of bone marrow mesenchymal stem cells from chronic aplastic anemia patients.
J Tradit Chin Med. 2012; 32(4):596-603 [PubMed]
OBJECTIVE: To explore the effect of kidney-reinforcing, blood-activating and stasis-removing recipes on adhesion molecule expression of bone marrow mesenchymal stem cells (MSCs) from patients with chronic aplastic anemia (CAA).
METHODS: We used three Traditional Chinese Medicine recipes, namely a kidney-reinforcing recipe (KRR), blood-activating and stasis-removing recipe (BASRR), and kidney-reinforcing, blood-activating and stasis-removing recipe (KRBASRR), and a normal saline control to prepare herbal medicine serum in Sprague Dawley rats. Thirty CAA patients were enrolled in the experimental group, including 17 kidney-Yang deficient patients and 13 kidney-Yin deficient patients. Ten healthy individuals were included in the control group. MSCs were isolated from bone marrow samples, and the cell density was observed to measure their proliferation ability by microscopy on days 2, 7, and 14 after isolation. In addition, the expression of adhesion molecules of bone marrow MSCs (CD106, CD49d, CD31 and CD44) were detected by flow cytometry after 48 h of treatment with the four different herbal medicine serums.
RESULTS: The proliferation of MSCs from kidney-Yang deficient and kidney-Yin deficient patients was weaker than that of MSCs from the control group. The expression of all adhesion molecules of bone marrow MSCs from CAA patients was obviously lower than that in the control group (P < 0.01). The expression of CD49d and CD31 in MSCs from patients with a kidney-Yin deficiency was lower than in those with a kidney-yang deficiency (P < 0.05 and P < 0.01, respectively). For kidney-Yang deficient patients, CD31 expression in the KRBASRR group was significantly higher than that in the BASRR group (P < 0.01), while CD44 in the KRBASRR group was significantly higher than that in both KRR and BASRR groups (P < 0.01). For kidney-Yin deficient patients, CD106 and CD49d expression in the KRBASRR group was obviously higher than that in the KRR group (P < 0.05), while CD31 and CD44 expression in the KRBASRR group was significantly higher than that in both KRR and BASRR groups (P < 0.05 and P < 0.01, respectively).
CONCLUSION: The bone marrow microenvironment in CAA patients is abnormal. The effect of KRBASRR may be better than that of KRR and BASRR for kidney-Yang deficient and kidney-Yin deficient patients by improving the expression levels of MSC adhesion molecules.


Shukla P, Rao A, Ghosh K, Vundinti BR
Identification of a novel large intragenic deletion in a family with Fanconi anemia: first molecular report from India and review of literature.
Gene. 2013; 518(2):470-5 [PubMed]
We report here an Indian case with Fanconi anemia (FA) presented with fever, pallor, short stature, hyperpigmentation and upper limb anomaly. Chromosome breakage analysis together with FANCD2 Western blot monoubiquitination assay confirmed the diagnosis as FA. Multiplex ligation-dependent probe amplification (MLPA) revealed a novel homozygous large intragenic deletion (exons 8-27 del) in the FANCA gene in the proband. His sib and parents were also analyzed and found to be heterozygous for the same mutation. We also reviewed the literature of FANCA large intragenic deletions found in FA patients from different countries and the mechanism involved in the formation of these deletions. To the best of our knowledge, this is the first molecular report from India on FA. The finding expands the mutation spectrum of the FANCA gene. Identification of the mutation confirms the diagnosis of FA at DNA level and helps in providing proper genetic counseling to the family.


Kottemann MC, Smogorzewska A
Fanconi anaemia and the repair of Watson and Crick DNA crosslinks.
Nature. 2013; 493(7432):356-63 [PubMed]
The function of Fanconi anaemia proteins is to maintain genomic stability. Their main role is in the repair of DNA interstrand crosslinks, which, by covalently binding the Watson and the Crick strands of DNA, impede replication and transcription. Inappropriate repair of interstrand crosslinks causes genomic instability, leading to cancer; conversely, the toxicity of crosslinking agents makes them a powerful chemotherapeutic. Fanconi anaemia proteins can promote stem-cell function, prevent tumorigenesis, stabilize replication forks and inhibit inaccurate repair. Recent advances have identified endogenous aldehydes as possible culprits of DNA damage that may induce the phenotypes seen in patients with Fanconi anaemia.


Shamshad GU, Ahmed S, Bhatti FA, Ali N
Mixed donor chimerism in non-malignant haematological diseases after allogeneic bone marrow transplantation.
J Coll Physicians Surg Pak. 2012; 22(12):765-8 [PubMed]
OBJECTIVE: To determine the frequency of mixed donor chimerism in patients of non-malignant haematological diseases after allogeneic bone marrow transplant.
STUDY DESIGN: A cross-sectional, observational study.
PLACE AND DURATION OF STUDY: Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from July 2010 to June 2011.
METHODOLOGY: Donor chimerism was assessed in patients of aplastic anaemia and beta-thalassaemia major who underwent allogeneic bone marrow transplantation (BMT). Peripheral blood samples were used to assess chimerism status by analysis of short tandem repeats (STR). In patients where pre-transplant blood sample was not available, swab of buccal mucosa was used for pre-transplant STR profile. A standard set of primers for STR markers were used and the amplified DNA was resolved by gel electrophoresis and stained with silver nitrate. The percentage of donor origin DNA was estimated by densitometer.
RESULTS: Out of 84 patients, 52 (62%) were males, while 32 (38%) were females. In patients of beta-thalassaemia major, 31 (62%) developed mixed donor chimerism (MC), 13 (26%) developed complete donor chimerism (CC) and 6 (12%) had graft failure. In aplastic anaemia, 17 patients (50%) achieved MC, 13 (38.2%) had CC and 4 (11.8%) developed graft failure. The combined frequency of mixed donor chimerism for both the diseases was 58.3%. D3S1358 was the most informative STR marker in these patients.
CONCLUSION: Majority of the studied patients developed mixed donor chimerism following bone marrow transplantation, whereas only a minor percentage of the patients had graft failure. Analysis of D3S1358 was the most informative in assessing donor chimerism in patients who underwent BMT.


O'Driscoll M
Diseases associated with defective responses to DNA damage.
Cold Spring Harb Perspect Biol. 2012; 4(12) [PubMed]
Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways.


Lee SE, Yahng SA, Cho BS, et al.
Improvement in hematopoiesis after iron chelation therapy with deferasirox in patients with aplastic anemia.
Acta Haematol. 2013; 129(2):72-7 [PubMed]
Iron overload due to regular transfusions of packed red cells can cause multiple organ damage. Iron chelation therapy (ICT) is important in patients with aplastic anemia (AA) who require blood transfusions as supportive management. With the introduction of the oral iron chelator deferasirox, ICT has become more widely available and feasible. We studied 4 adult AA patients who had transfusion-induced iron overload and showed hematological improvement after ICT with oral deferasirox. Following deferasirox treatment, hemoglobin increased and serum ferritin levels decreased, and the patients subsequently became transfusion independent. Our experience raises the possibility of the potential benefit of ICT on hematopoiesis. Further long-term studies in larger patient cohorts are needed to clarify the effect of the restoration of hematopoiesis after iron chelation therapy.


Smith AR, Wagner JE
Current clinical management of Fanconi anemia.
Expert Rev Hematol. 2012; 5(5):513-22 [PubMed]
Fanconi anemia (FA) is a heterogeneous disease characterized by spontaneous chromosomal breaks and abnormal DNA repair. Major clinical problems in FA include congenital abnormalities, endocrinopathies, early onset bone marrow failure and increased risk of myelodysplastic syndrome, acute leukemia and solid tumors. To date, 15 different genes have been shown to cause FA, all of which have some role in DNA double-strand break repair. Very few strict genotype-phenotype associations have been identified and clinical manifestations vary widely from patient to patient, most likely due to modifier genes, environment and chance effects. Hematopoietic stem cell transplantation is the only proven cure for the hematopoietic manifestations of FA and aggressive lifelong surveillance for solid tumors is essential.


Taskinen M, Toiviainen-Salo S, Lohi J, et al.
Hypoplastic anemia in cartilage-hair hypoplasia-balancing between iron overload and chelation.
J Pediatr. 2013; 162(4):844-9 [PubMed]
OBJECTIVE: To evaluate the severity of iron overload and the success of iron chelation therapy in patients with cartilage-hair hypoplasia (CHH) and hypoplastic anemia, with particular focus on adverse effects of iron chelators.
STUDY DESIGN: Four of the 23 presently surviving Finnish patients with CHH under 18 years of age are dependent on regular red blood cell transfusions. Their hospital records were reviewed for history of anemia and chelation therapy. Cumulative iron load from transfusions was calculated. Efficacy of the chelation therapy was evaluated biochemically and by liver iron content assessments.
RESULTS: At the introduction of iron chelation, the patients had received on average 99 (37-151) transfusions; the mean cumulative iron overload was 4640 (800-8200) mg, the annual iron accumulation rate 0.35 (0.25-0.41) mg/kg/d, and the mean plasma ferritin was 2896 (1217-6240) μg/L. Liver iron content, determined by biopsy in 3 patients, was on average 20.0 (6.6-30.0) mg/g liver dry weight. All patients, except 1 with Hirschsprung disease, tolerated deferoxamine, deferiprone, and deferasirox therapy well, showing only mild adverse effects typical for the agents. Plasma ferritin levels and liver magnetic resonance imaging T2* of iron overload showed successful chelation.
CONCLUSION: Iron chelation is well tolerated in patients with CHH, with possible exception of patients with Hirschsprung disease. Successful chelation will prepare for hematopoietic stem cell transplantation in patients with CHH with persistent transfusion dependency.


Brock K, Goldenberg N, Graham DK, et al.
Moderate aplastic anemia in children: preliminary outcomes for treatment versus observation from a single-institutional experience.
J Pediatr Hematol Oncol. 2013; 35(2):148-52 [PubMed]
INTRODUCTION: Because of the variety of definitions used to describe moderate aplastic anemia (MAA), we review our institutional experience period with patients who met a proposed set of criteria for this disorder. On an exploratory basis, we sought to evaluate the influence of treatment with immunosuppressive therapy (IST) versus observation on long-term outcomes.
MATERIALS AND METHODS: Records from 1999 to 2010 were screened for patients who met the criteria for MAA: (1) bone marrow cellularity of 20% to 50%; (2) cytopenias in at least 1 cell line (absolute neutrophil count<1000/µL, hemoglobin<9 g/dL, platelet count<100,000/µL); (3) mean corpuscular volume ≥90; (4) persistence >6 months; and (5) negative Fanconi studies. Data were collected for patient/disease characteristics, treatments, and outcomes.
RESULTS: Eight patients met the criteria for MAA. Three of 8 patients received IST. Of 3 patients who received IST, complete response was observed in 2 and transfusion independence in 1, as compared with 2 of 5 and 3 of 5 in the group who were observed without IST. Median duration of follow-up was 48 months.
DISCUSSION: As several patients spontaneously resolved, and none developed severe aplastic anemia, acute myelogenous leukemia, or myelodysplastic syndrome, the criteria used here may identify a group of children with favorable prognosis who can be managed supportively.


Kee Y, D'Andrea AD
Molecular pathogenesis and clinical management of Fanconi anemia.
J Clin Invest. 2012; 122(11):3799-806 [PubMed] Free Access to Full Article
Fanconi anemia (FA) is a rare genetic disorder associated with a high frequency of hematological abnormalities and congenital anomalies. Based on multilateral efforts from basic scientists and clinicians, significant advances in our knowledge of FA have been made in recent years. Here we review the clinical features, the diagnostic criteria, and the current and future therapies of FA and describe the current understanding of the molecular basis of the disease.


Li Y, Sheng Z, Niu S, et al.
Rapid and complete reconstitution of autologous haemopoiesis after cord blood infusion in treatment-naive patients with severe aplastic anemia receiving high-dose cyclophosphamide/ATG therapy.
Eur J Haematol. 2013; 90(1):45-50 [PubMed]
Although high-dose cyclophosphamide seems to achieve durable complete remission, there are still concerns about its too much early toxicity. So, we designed a clinical study to investigate the effects of high-dose cyclophosphamide/ATG combined with cord blood infusion as first-line therapy for patients with severe aplastic anemia. Patients and Method: Between January 2003 and September 2007, we treated 16 treatment-naive patients with severe aplastic anemia with cord blood infusion after high-dose cyclophosphamide (50 mg/kg/d × 2) and rabbit antithymocyte globulin (3 mg/kg/d × 5) therapy. Results: Although only one patient had durable full donor engraftment, 14 of the enrolled 16 patients had rapid autologous hematopoietic recovery. The median recovery time for neutrophils and platelets was only 23 and 37 d after infusion of cord blood. Of the 15 responding patients, all patients achieved treatment-free remission: nine patients met the criteria for a complete remission; six patients achieved a partial remission. Conclusion: Infusion of cord blood after high-dose cyclophosphamide/ATG resulted in a rapid autologous hematologic recovery and a high response rate in patients with treatment-naive patients with severe aplastic anemia. These promising results merit further investigation and confirmation on a larger number of patients.


Kim Y, Spitz GS, Veturi U, et al.
Regulation of multiple DNA repair pathways by the Fanconi anemia protein SLX4.
Blood. 2013; 121(1):54-63 [PubMed] Article available free on PMC after 03/01/2014
SLX4, the newly identified Fanconi anemia protein, FANCP, is implicated in repairing DNA damage induced by DNA interstrand cross-linking (ICL) agents, topoisomerase I (TOP1) inhibitors, and in Holliday junction resolution. It interacts with and enhances the activity of XPF-ERCC1, MUS81-EME1, and SLX1 nucleases, but the requirement for the specific nucleases in SLX4 function is unclear. Here, by complementing a null FA-P Fanconi anemia cell line with SLX4 mutants that specifically lack the interaction with each of the nucleases, we show that the SLX4-dependent XPF-ERCC1 activity is essential for ICL repair but is dispensable for repairing TOP1 inhibitor-induced DNA lesions. Conversely, MUS81-SLX4 interaction is critical for resistance to TOP1 inhibitors but is less important for ICL repair. Mutation of SLX4 that abrogates interaction with SLX1 results in partial resistance to both cross-linking agents and TOP1 inhibitors. These results demonstrate that SLX4 modulates multiple DNA repair pathways by regulating appropriate nucleases.


Gerds AT, Scott BL
Last marrow standing: bone marrow transplantation for acquired bone marrow failure conditions.
Curr Hematol Malig Rep. 2012; 7(4):292-9 [PubMed] Article available free on PMC after 01/12/2013
Paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome are a spectrum of acquired marrow failure, having a common pathologic thread of both immune dysregulation and the development of abnormal hematopoiesis. Allogeneic hematopoietic cell transplantation plays a critical role in the treatment of these disorders and, for many patients, is the only treatment modality with demonstrated curative potential. In recent years, there have been many breakthroughs in the understanding of the pathogenesis of these uncommon disorders. The subsequent advances in non-transplant therapies, along with concurrent improvement in outcomes after hematopoietic cell transplantation, necessitate continual appraisal of the indications, timing, and approaches to transplantation for acquired marrow failure syndromes. We review here contemporary and critical new findings driving current treatment decisions.


Li N, Song Y, Zhou J, Fang B
Arsenic trioxide improves hematopoiesis in refractory severe aplastic anemia.
J Hematol Oncol. 2012; 5:61 [PubMed] Article available free on PMC after 01/12/2013
We investigated the efficacy of arsenic trioxide (ATO) in patients with refractory severe aplastic anemia (SAA). A total of 5 consecutive adults were enrolled. The patients received ATO at a dose of 0.15 mg/kg intravenously daily for 5 days every week for 8 weeks. If necessary, a second course was performed after an interval of one week. All patients achieved clinically significant responses to ATO. The overall complete response rate and overall response rate at 17 weeks were 60% (3/5) and 100%(5/5), respectively. So treatment with ATO may be a feasible approach in patients with refractory SAA.


Taylor S, Hu C, Pan DH, Manwani D
Treatment of acquired aplastic anemia in patients with acute liver failure occurring concurrently: a case series.
J Pediatr Hematol Oncol. 2012; 34(8):e349-52 [PubMed]
The association between acquired aplastic anemia (AA) and hepatitis/acute liver failure has been well characterized as AA temporally after the presentation of acute hepatitis. In this case series we report 2 cases of patients who present with AA occurring simultaneously with the development of acute liver failure. This is among only a few reported cases known to date in which AA occurs simultaneously with impending liver failure. More importantly, this is the first report that demonstrates the feasibility of administering immunosuppressive therapy before complete resolution of the hepatic dysfunction and with excellent results. Both of our cases avoided orthotopic liver transplantation through the use of timely immunosuppressive therapy, demonstrating the potential role of medical management to avoid transplantation in these patients. Previous studies have suggested a link between an unidentified viral process and immune dysregulation that may lead to the development of AA after acute hepatitis. These 2 cases support the rationale that in our patients the 2 disease processes may share a common etiology and encourage further research into the complex pathogenic mechanism affecting these 2 different organ systems at varying points in time.


Horos R, von Lindern M
Molecular mechanisms of pathology and treatment in Diamond Blackfan Anaemia.
Br J Haematol. 2012; 159(5):514-27 [PubMed]
Diamond Blackfan Anaemia (DBA) is a rare congenital pure red cell aplasia that may be associated with facio-skeletal developmental defects. The disease is caused by mutations in one of at least ten ribosomal proteins, which results in haploinsufficiency and an imbalance between the synthesis of rRNA and ribosomal proteins during ribosome biogenesis. Such imbalance results in stabilization and activation of the tumour suppressor gene TP53. The loss of ribosomes also results in reduced mRNA translation capacity, and may affect translation of specific erythroid transcripts more than average. The contribution of these two mechanisms to impaired erythropoiesis is discussed. The most effective and relatively safe therapy is treatment with glucocorticoid hormone, but responsiveness differs between patients. The molecular and cellular mechanisms involved in treatment are discussed in the context of DBA.


Sarashina T, Yoshida M, Iguchi A, et al.
Risk factor analysis of bloodstream infection in pediatric patients after hematopoietic stem cell transplantation.
J Pediatr Hematol Oncol. 2013; 35(1):76-80 [PubMed]
Bloodstream infection (BSI) is a recognized cause of morbidity and mortality in children after hematopoietic stem cell transplantation (HSCT). However, there are limited reports on BSI after HSCT in pediatric patients in multiple centers. This study was a retrospective cohort analysis of consecutive patients who underwent allogeneic and autologous HSCT at the Department of Paediatrics, Hokkaido University Hospital, between 1988 and 2009; the Department of Paediatrics, Sapporo Hokuyu Hospital, between 2007 and 2009; and the Department of Paediatrics, Asahikawa Medical University, between 1989 and 2009. A total of 277 patients underwent HSCT during the study period. In this multicenter analysis, cases of BSI after HSCT were recorded in the early posttransplant period (within the first 100 d), and BSI was observed in 24 of 277 HSCT patients. Multivariate analysis showed that nonmalignant disease was an independent factor associated with BSI after HSCT (hazard ratio 6.3 for aplastic anemia or Wiskott-Aldrich syndrome patients; confidence interval, 1.4-12.8; P = 0.012). We conclude that aplastic anemia and Wiskott-Aldrich syndrome were the novel risk factors for BSI in pediatric patients after HSCT.


Ahmed P, Chaudhry QU, Raza S, et al.
Outcome of allogeneic haematopoietic stem cell transplantation in aplastic anaemia.
J Coll Physicians Surg Pak. 2012; 22(9):553-9 [PubMed]
OBJECTIVE: To analyze factors associated with survival, rejection and graft versus host disease in aplastic anaemia patients undergoing allogeneic haematopoietic stem cell transplantation (SCT) from HLA matched sibling donors.
STUDY DESIGN: Analytical study.
PLACE AND DURATION OF STUDY: Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan from July 2001 to June 2010. Methodology: Consecutive aplastic anaemia (AA) patients undergoing haematopoietic stem cell transplantation from HLA-matched sibling donors at this centre were included in this study. Potential factors affecting overall survival, rejection, disease-free survival and graft versus host disease were analyzed. Survival analysis was done by Kaplan-Meier method. Cox regression model was applied for multivariate analysis.
RESULTS: Ninety male and thirty-five female patients with AA were included in the study. Median age was 18 years. Conditioning regimens used were cyclophosphamide (Cy) plus antilymphocyte globulin (ALG) or antithymocyte globulin (ATG), fludarabine (FLU) +Cy+ATG, Campath 1-H +Cy in 89, 30 and 6 cases respectively. GVHD prophylaxis used was ciclosporin (CSA) plus prednisolone and short methotrexate in 81 while 44 received CSA plus prednisolone. At a median follow-up of 1185 days OS and DFS were 84% and 78% respectively. Factors associated with better OS were male sex, Flu/Cy/ATG conditioning and use of bone marrow as stem cell source.
CONCLUSION: Flu/Cy/ATG conditioning regimen, bone marrow as stem cell source and CSA, prednisolone and short methotrexate regimen were associated with better survival in AA.


Nielsen M, Vermont CL, Aten E, et al.
Deletion of the 3q26 region including the EVI1 and MDS1 genes in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia.
J Med Genet. 2012; 49(9):598-600 [PubMed]
BACKGROUND: Gene-targeting studies in mice have revealed a key role for EVI1 protein in the maintenance of haematopoiesis, and argue in favour of a gene dosage requirement for EVI1 in the regulation of haematopoietic stem cells. Furthermore, a fusion transcript of MDS1 and EVI1 has been shown to play a critical role in maintaining long-term haematopoietic stem cell function. Inappropriate activation of EVI1, usually due to a translocation, is a well known and unfavourable change in several myeloid malignancies. It is not known whether haploinsufficiency of any of these genes leads to disease in humans.
METHODS: SNP array analysis in a patient with in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia
RESULTS AND CONCLUSIONS: We report for the first time a constitutional deletion encompassing the EVI1 and MDS1 genes in a human, and argue that the deletion causes congenital bone marrow failure in this patient.


Neuwirtova R, Fuchs O, Holicka M, et al.
Transcription factors Fli1 and EKLF in the differentiation of megakaryocytic and erythroid progenitor in 5q- syndrome and in Diamond-Blackfan anemia.
Ann Hematol. 2013; 92(1):11-8 [PubMed]
Friend leukemia virus integration 1 (Fli1) and erythroid Krüppel-like factor (EKLF) participate under experimental conditions in the differentiation of megakaryocytic and erythroid progenitor in cooperation with other transcription factors, cytokines, cytokine receptors, and microRNAs. Defective erythropoiesis with refractory anemia and effective megakaryopoiesis with normal or increased platelet count is typical for 5q- syndrome. We decided to evaluate the roles of EKLF and Fli1 in the pathogenesis of this syndrome and of another ribosomopathy, Diamond-Blackfan anemia (DBA). Fli1 and EKLF mRNA levels were examined in mononuclear blood and bone marrow cells from patients with 5q- syndrome, low-risk MDS patients with normal chromosome 5, DBA patients, and healthy controls. In 5q- syndrome, high Fli1 mRNA levels in the blood and bone marrow mononuclear cells were found. In DBA, Fli1 expression did not differ from the controls. EKLF mRNA level was significantly decreased in the blood and bone marrow of 5q- syndrome and in all DBA patients. We propose that the elevated Fli1 in 5q- syndrome protects megakaryocytic cells from ribosomal stress contrary to erythroid cells and contributes to effective though dysplastic megakaryopoiesis.


Mavroudi I, Papadaki HA
Genetic associations in acquired immune-mediated bone marrow failure syndromes: insights in aplastic anemia and chronic idiopathic neutropenia.
Clin Dev Immunol. 2012; 2012:123789 [PubMed] Article available free on PMC after 01/12/2013
Increasing interest on the field of autoimmune diseases has unveiled a plethora of genetic factors that predispose to these diseases. However, in immune-mediated bone marrow failure syndromes, such as acquired aplastic anemia and chronic idiopathic neutropenia, in which the pathophysiology results from a myelosuppressive bone marrow microenvironment mainly due to the presence of activated T lymphocytes, leading to the accelerated apoptotic death of the hematopoietic stem and progenitor cells, such genetic associations have been very limited. Various alleles and haplotypes of human leucocyte antigen (HLA) molecules have been implicated in the predisposition of developing the above diseases, as well as polymorphisms of inhibitory cytokines such as interferon-γ, tumor necrosis factor-α, and transforming growth factor-β1 along with polymorphisms on molecules of the immune system including the T-bet transcription factor and signal transducers and activators of transcription. In some cases, specific polymorphisms have been implicated in the outcome of treatment on those patients.


Lee HJ, Park S, Kang HJ, et al.
A case report of Fanconi anemia diagnosed by genetic testing followed by prenatal diagnosis.
Ann Lab Med. 2012; 32(5):380-4 [PubMed] Article available free on PMC after 01/12/2013
Fanconi anemia (FA) is a rare genetic disorder affecting multiple body systems. Genetic testing, including prenatal testing, is a prerequisite for the diagnosis of many clinical conditions. However, genetic testing is complicated for FA because there are often many genes that are associated with its development, and large deletions, duplications, or sequence variations are frequently found in some of these genes. This study describes successful genetic testing for molecular diagnosis, and subsequent prenatal diagnosis, of FA in a patient and his family in Korea. We analyzed all exons and flanking regions of the FANCA, FANCC, and FANCG genes for mutation identification and subsequent prenatal diagnosis. Multiplex ligation-dependent probe amplification analysis was performed to detect large deletions or duplications in the FANCA gene. Molecular analysis revealed two mutations in the FANCA gene: a frameshift mutation c.2546delC and a novel splice-site mutation c.3627-1G>A. The FANCA mutations were separately inherited from each parent, c.2546delC was derived from the father, whereas c.3627-1G>A originated from the mother. The amniotic fluid cells were c.3627-1G>A heterozygotes, suggesting that the fetus was unaffected. This is the first report of genetic testing that was successfully applied to molecular diagnosis of a patient and subsequent prenatal diagnosis of FA in a family in Korea.


Yue LZ, Shao ZH
Research progress on the red cell diseases in China.
Chin Med J (Engl). 2012; 125(15):2746-51 [PubMed]
In recent years, there have been lots of progresses in the studies on red cell diseases in China, especially bone marrow failure diseases including immuno-related pancytopenia, aplastic anemia, myelodysplastic syndrome, and paroxymal nocturnal hemoglobinuria. Numerous laboratory experiments as well as clinical researches have been carried out by Chinese hematologists, which brought about much clearer pathogenesis, more rational diagnosis methods and more effective therapies for red cell diseases.


Yuan C, Xu N, Liao J
Switch of FANCL, a key FA-BRCA component, between tumor suppressor and promoter by alternative splicing.
Cell Cycle. 2012; 11(18):3356 [PubMed] Article available free on PMC after 01/12/2013
Comment on: Panneerselvam J, et al. Cell Cycle 2012; 11:2947-55.


Cui X, Liu F, Wang JQ, et al.
Complete sequence analysis of mitochondrial DNA of aplastic anemia patients.
Genet Mol Res. 2012; 11(3):2130-7 [PubMed]
This study was primarily undertaken to test the hypothesis that mitochondrial DNA (mtDNA) mutations may be associated with aplastic anemia (AA). We analyzed mtDNA sequences from 15 patients with AA. The samples were obtained from bone marrow, and patients' oral epithelial cells were collected for normal tissue comparison. Total DNA was amplified by PCR after extraction, and these segments were then sent for sequencing. The results were compared with those of oral epithelial tissues as well as mtDNA sequences in the revised Cambridge Reference Sequence (rCRS) database. We detected 61 heteroplasmic mutations in 11 genes, including those encoding NADH dehydrogenase (ND)1-2 and 4-6, tRNA glutamic acid (TRNE), ribosomal RNA (RNR) 1 and 2, cytochrome c oxidase (COX1), cytochrome b (CYTB), and tRNA glycine (TRNG); mutation rates were particularly high in ND2 (34.4%) and ND4 (21.3%) in the patients' mtDNA genomes. The products of these genes are involved in oxidation in the respiratory chain, and a large number of homoplasmic mutations were found. Interestingly, these 162 polymorphisms were mostly in the D-loop DNA structure (54.3%), in which numerous mutations associated with leukemia and myelodysplastic syndromes are found. We conclude that functional impairment of the mitochondrial respiratory chain induced by mutation may be an important reason for hematopoietic failure in AA patients.


Salewsky B, Schmiester M, Schindler D, et al.
The nuclease hSNM1B/Apollo is linked to the Fanconi anemia pathway via its interaction with FANCP/SLX4.
Hum Mol Genet. 2012; 21(22):4948-56 [PubMed]
The recessive genetic disorder Fanconi anemia (FA) is clinically characterized by congenital defects, bone marrow failure and an increased incidence of cancer. Cells derived from FA patients exhibit hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. We have earlier reported a similar cellular phenotype for human cells depleted of hSNM1B/Apollo (siRNA). In fact, hSNM1B/Apollo has a dual role in the DNA damage response and in generation and maintenance of telomeres, the latter function involving interaction with the shelterin protein TRF2. Here we find that ectopically expressed hSNM1B/Apollo co-immunoprecipitates with SLX4, a protein recently identified as a new FA protein, FANCP, and known to interact with several structure-specific nucleases. As shown by immunofluorescence analysis, FANCP/SLX4 depletion (siRNA) resulted in a significant reduction of hSNM1B/Apollo nuclear foci, supporting the functional relevance of this new protein interaction. Interestingly, as an additional consequence of FANCP/SLX4 depletion, we found a reduction of cellular TRF2, in line with its telomere-related function. Finally, analysis of human cells following double knockdown of hSNM1B/Apollo and FANCP/SLX4 indicated that they function epistatically. These findings further substantiate the role of hSNM1B/Apollo in a downstream step of the FA pathway during the repair of DNA ICLs.


This page last updated: 22nd May 2013
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