scholarly journals Genetic Associations in Acquired Immune-Mediated Bone Marrow Failure Syndromes: Insights in Aplastic Anemia and Chronic Idiopathic Neutropenia

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Irene Mavroudi ◽  
Helen A. Papadaki
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Transforming Growth Factor ◽  
Bone Marrow Failure ◽  
Genetic Associations ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes ◽  
Immune Mediated ◽  
Chronic Idiopathic Neutropenia ◽  
Activated T Lymphocytes

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.

scholarly journals Secondary CNL after SAA reveals insights in leukemic transformation of bone marrow failure syndromes

2020 ◽  
Vol 4 (21) ◽  
pp. 5540-5546
Author(s):  
Laurent Schmied ◽  
Patricia A. Olofsen ◽  
Pontus Lundberg ◽  
Alexandar Tzankov ◽  
Martina Kleber ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Failure ◽  
Driver Mutations ◽  
Leukemic Transformation ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes ◽  
Proinflammatory Responses ◽  
Stem And Progenitor Cells

Abstract Acquired aplastic anemia and severe congenital neutropenia (SCN) are bone marrow (BM) failure syndromes of different origin, however, they share a common risk for secondary leukemic transformation. Here, we present a patient with severe aplastic anemia (SAA) evolving to secondary chronic neutrophilic leukemia (CNL; SAA-CNL). We show that SAA-CNL shares multiple somatic driver mutations in CSF3R, RUNX1, and EZH2/SUZ12 with cases of SCN that transformed to myelodysplastic syndrome or acute myeloid leukemia (AML). This molecular connection between SAA-CNL and SCN progressing to AML (SCN-AML) prompted us to perform a comparative transcriptome analysis on nonleukemic CD34high hematopoietic stem and progenitor cells, which showed transcriptional profiles that resemble indicative of interferon-driven proinflammatory responses. These findings provide further insights in the mechanisms underlying leukemic transformation in BM failure syndromes.

scholarly journals The predictive value of PNH clones, 6p CN-LOH, and clonal TCR gene rearrangement for aplastic anemia diagnosis

2021 ◽  
Vol 5 (16) ◽  
pp. 3216-3226
Author(s):  
Yash B. Shah ◽  
Salvatore F. Priore ◽  
Yimei Li ◽  
Chi N. Tang ◽  
Peter Nicholas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Predictive Value ◽  
Bone Marrow Failure ◽  
Neutral Loss ◽  
Cell Receptor ◽  
Laboratory Findings ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes ◽  
Stem And Progenitor Cells

Abstract Acquired aplastic anemia (AA) is a life-threatening bone marrow aplasia caused by the autoimmune destruction of hematopoietic stem and progenitor cells. There are no existing diagnostic tests that definitively establish AA, and diagnosis is currently made via systematic exclusion of various alternative etiologies, including inherited bone marrow failure syndromes (IBMFSs). The exclusion of IBMFSs, which requires syndrome-specific functional and genetic testing, can substantially delay treatment. AA and IBMFSs can have mimicking clinical presentations, and their distinction has significant implications for treatment and family planning, making accurate and prompt diagnosis imperative to optimal patient outcomes. We hypothesized that AA could be distinguished from IBMFSs using 3 laboratory findings specific to the autoimmune pathogenesis of AA: paroxysmal nocturnal hemoglobinuria (PNH) clones, copy-number–neutral loss of heterozygosity in chromosome arm 6p (6p CN-LOH), and clonal T-cell receptor (TCR) γ gene (TRG) rearrangement. To test our hypothesis, we determined the prevalence of PNH, acquired 6p CN-LOH, and clonal TRG rearrangement in 454 consecutive pediatric and adult patients diagnosed with AA, IBMFSs, and other hematologic diseases. Our results indicated that PNH and acquired 6p CN-LOH clones encompassing HLA genes have ∽100% positive predictive value for AA, and they can facilitate diagnosis in approximately one-half of AA patients. In contrast, clonal TRG rearrangement is not specific for AA. Our analysis demonstrates that PNH and 6p CN-LOH clones effectively distinguish AA from IBMFSs, and both measures should be incorporated early in the diagnostic evaluation of suspected AA using the included Bayesian nomogram to inform clinical application.

Comprehensive Analysis of Telomere Biology in Patients with Aplastic Anemia and Hypoplastic Myelodysplastic Syndrome: Further Evidence for a Common Mechanism

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2858-2858
Author(s):  
Anne-Sophie Bouillon ◽  
Monica S. Ferreira ◽  
Benjamin Werner ◽  
Sebastian Hummel ◽  
Jens P. Panse ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Common Mechanism ◽  
Telomere Shortening ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes ◽  
The Individual

Abstract Introduction: Acquired aplastic anemia (AA) is typically characterized by pancytopenia and bone marrow (BM) failure mostly due to an autoimmune attack against the hematopoietic stem cell compartment. Thus, AA patients frequently respond to immunosuppressive therapy (IST). Hypoplastic myelodysplastic syndrome (hMDS) frequently mimics clinical and morphological features of AA and proper clinical discrimination of hMDS from AA sometimes remains difficult. Interestingly, some cases of hMDS respond at least partially to IST and on the other hand, AA can clonally evolve to hMDS. Telomeres shorten with each cell division and telomere length (TL) reflects the replicative potential of somatic cells. Whereas it is proposed that TL can to some degree discriminate hereditary subtypes of bone marrow failure syndromes from classical acquired forms, the role of TL for disease pathogenesis in hMDS remains unclear. In this study, we therefore aimed to investigate accelerated TL shortening as a possible (bio-)marker to distinguish hMDS from AA. Patients and Methods: TL of BM biopsies at diagnosis of 12 patients with hMDS and 15 patients with AA treated in the University Hospital Düsseldorf were analyzed. Mean age was 45.2 years in AA patients and 65.2 years in patients with hMDS. Confocal Q-FISH protocol was used for TL measurement as published previously (Blood, 2012). TL analysis was performed in single-blinded fashion. 28 patients (range 18-80 years) with newly diagnosed M. Hodgkin without BM affection were used as controls for linear regression and calculation of age-adapted TL difference. For the analysis of the data, we made use of a recently developed mathematical model of TL distribution on the stem cell level allowing us to extrapolate mean TL shortening per year (TS/y) based on the individual TL distributions of captured BM biopsies. Results: Using the controls to adjust for age, we found that age-adapted TL was significantly shortened both in patients with AA (median: -2.96 kb, range -4.21 to 0.26, p=0.001) and patients with hMDS (median: -2.26, range -3.85 to -0.64, p=0.005). In direct comparison, telomere shortening was more accelerated in patients with AA as compared to hMDS (p=0.048). Next, we analyzed the TL shortening per year (TS/y) based on the individual telomere distribution. Calculating the extrapolated TL shortening per year (TS/y), we found significant increased TS/y in AA patients (mean±SD: 235,8 bp/y±202,9, p=0.001) and hMDS patients (120,5±41,7 bp/y, p=0.0001) compared to controls (37,5±18,9 bp/y). Interestingly, the extrapolated rate of TS/y remained stable at different ages in hMDS patients as observed in healthy controls. In contrast, TS/y in AA patients showed a strong age-dependence with a maximum of TS/y in patients younger than 30 years (R²=0.42, p=0.008). Finally, we set to test whether TS/y can be used to identify AA or hMDS patients. Using 150 bp TS/y as a cut-off (4-fold the mean of controls), we found significantly more AA patients (10/15, 66.7%) had accelerated TL shortening compared to hMDS (1/12, 8.3% p=0.005). Conclusion: We provide first retrospective data on TL in patients with hMDS using confocal Q-FISH. Age-adapted TL is significantly shorter in patients with AA compared to hMDS. Interestingly, telomere shortening per year is both significantly increased in AA as compared to hMDS patients as well as in both groups compared to controls. The rate of telomere shortening TS/y might represent a new marker in patients with bone marrow failure syndromes that allows to discriminate AA from hMDS patients pending prospective validation. Disclosures No relevant conflicts of interest to declare.

Development of Paroxysmal Nocturnal Hemoglobinuria in Children with Aplastic Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1499-1499 ◽  
Author(s):  
Atsushi Narita ◽  
Hideki Muramatsu ◽  
Yusuke Okuno ◽  
Yuko Sekiya ◽  
Kyogo Suzuki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Subsequent Development ◽  
Poor Quality ◽  
Targeted Sequencing ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes

Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disease of hematopoietic stem cells resulting from a somatic mutation in the PIGA gene. PNH frequently manifests in association with aplastic anemia (AA), in which PIGA mutations are believed to enable escape from the immune-mediated destruction by pathogenic T cells. Recent studies using next-generation sequencing have revealed that frequent somatic PIGA mutationsin AA patients are associated with a better response to IST and prognosis (Yoshizato et al N Engl J Med. 2015; 373: 35-47). However, clinical PNH is a progressive and life-threatening disease driven by chronic hemolysis that leads to thrombosis, renal impairment, poor quality of life, and death. Large studies in adults have reported that clinical PNH developed in 10%-25% of AA patients; however; the frequency of clinical PNH in children with AA has rarely been described. Here we aimed to elucidate the pathological link between PNH and AA in children. Methods: In total, 57 children (35 boys and 22 girls) diagnosed with acquired AA at our hospital between 1992 and 2010 were retrospectively studied. Patients who underwent hematopoietic stem cell transplantation as first-line treatment within 1 year after AA diagnosis and those with clinical PNH at AA diagnosis were excluded. Flow cytometry (FCM) was used to detect PNH CD13+/CD55−/CD59− granulocytes and PNH glycophorin A+/CD55−/CD59− red blood cells (RBCs). Clinical PNH was defined as the presence of intravascular hemolysis and ≥5% PNH granulocytes or PNH RBCs. Minor PNH clones were defined as those with >0.005% PNH granulocytes or >0.010% PNH RBCs. We performed targeted sequencing of bone marrow samples from patients with clinical PNH that were obtained at 2 time points: at AA diagnosis and after PNH development. The panel of 184 genes for targeted sequencing included most of the genes known to be mutated in inherited bone marrow failure syndromes and myeloid cancers, as well as PIGA. Results: The median patient age at AA diagnosis was 9.3 (1.2-17.8) years, and the median follow-up period was 123 (2-228) months. A total of 43 patients were screened for PNH clones by FCM after AA diagnosis, and 21 of these with minor PNH clones were identified. The median percentages of PNH granulocytes and PNH RBCs were 0.001% (0.000%-4.785%) and 0.000% (0.000%-3.829%), respectively. During follow-up, 5 patients developed clinical PNH after adolescence (15-22 years of age). The median time between AA diagnosis and PNH development was 4.9 (3.3-7.9) years. All clinical PNH patients were treated with IST for AA, and complete and partial response after 6 months were achieved in 1 and 4 patients, respectively. Gross hemoglobinuria was present in all clinical PNH patients, but thrombosis was not observed. The size of PNH clones varied greatly among patients: PNH granulocytes and PNH RBCs were 42.96% (10.04%-59.50%) and 48.87% (15.02%-90.80%), respectively. Oral cyclosporine A and intravenous eculizumab were administered to 3 and 1 patients, respectively; all patients showed sustained response as indicated by improvement in gross hemoglobinuria and normal blood counts after treatment. The remaining 1 patient underwent bone marrow transplantation from the HLA-identical mother and was alive without any complications. Overall, the 10-year probability of developing clinical PNH was 10.2% (95%CI, 3.6-20.7). Among 43 patients screened for PNH clones at AA diagnosis, the 10-year cumulative clinical PNH incidence was significantly higher in patients with minor PNH clones than in those without minor PNH clones at AA diagnosis [29% (95% CI, 10%-51%) vs. 0% (95% CI, 0%-0%); p = 0.015]. Among all clinical PNH patients, a total of 8 somatic PIGA mutations were detected (missense, 2; splice site, 2; and frameshift, 4). However, PIGA mutations were not detected at AA diagnosis even in patients who subsequently developed clinical PNH. Conclusion: In our cohort, the percentage of patients who eventually developed clinical PNH was comparable to that reported in adults in a previous study. Furthermore, the current study showed that the presence of minor PNH clones at AA diagnosis was a risk factor for the subsequent development of clinical PNH, although the clones were not detected by targeted sequencing. Thus, pediatric AA patients with PNH clones at AA diagnosis should undergo long-term periodic monitoring for potential clinical PNH development. Disclosures Kojima: SANOFI: Honoraria, Research Funding.

Decreased Numbers of Tregs in Aplastic Anemia Is Detected by Immunohistochemistry and Flow Cytometry.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1703-1703
Author(s):  
Bianca Serio ◽  
Ziad Peerwani ◽  
Ramon Tiu ◽  
Jennifer Powers ◽  
Erik Hsi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cells ◽  
Aplastic Anemia ◽  
Immunohistochemical Staining ◽  
Bone Marrow Failure ◽  
Peripheral Tolerance ◽  
Hematopoietic Stem ◽  
Central Tolerance ◽  
Immune Mediated

Abstract Idiopathic aplastic anemia (AA) is characterized by immune-mediated destruction of hematopoietic stem cells, leading to peripheral pancytopenia. Immune pathogenesis in AA is supported by experimental data, as well as clinical observations and may be related to the breach of peripheral or central tolerance. Regulatory T cells (Treg) constitute one of the most important mechanisms of central tolerance engaged in the down-modulation of autoreactive T cells. Tregs have been found to be reduced in several autoimmune diseases and decreased frequencies of Tregs were also reported in AA and MDS. Overexpression of the high affinity IL-2 receptor alpha chain (CD25) and the forkhead family transcription factor P3 (FoxP3), required for the development and function of Tregs, serve as phenotypic markers for Tregs. We investigated Treg levels in a cohort of AA patients (N=21) and healthy individuals (N=15); flow cytometric quantification of Treg was carried out after surface/intracellular staining of whole blood for Treg markers (CD3, CD4, CD25, FoxP3). After proper gating (light scatter properties, CD3, CD4, CD25), CD4+ T cells were subdivided into CD25−, CD25int and CD25hi populations, and the co-expression of CD25hi and Foxp3 was analyzed. In comparison to controls, AA patients (N=12) show not only lower frequencies of CD4+CD25hi+ T cells within the total lymphocyte population (median 0.07% vs. 0.21%; p=.03), but also absolute lower absolute numbers (1.31/uL vs. 5.78/uL, p=.0002). Similarly, CD4+CD25hi+FoxP3+ T cells were found to be depressed in untreated AA patients in comparison to controls (median 0.07% vs. 0.21% and 1.06/uL vs. 4.76/uL; p=.03 and p=.003). While Tregs were lower in patients with active disease unresponsive to immunosuppressive treatment (responder 0.1% vs non responder 0.07%, CD4+CD25hi Tcells, p=.02), serial testing performed in 6 patients treated with ATG/CsA did not reveal correlation between hematologic improvement and recovery of Treg numbers. When double immunohistochemical staining for CD3 and Foxp3 was performed in pre-treatment bone marrow core biopsies of AA patients (N=3) and controls (N=2) a mean of 3 CD3+Foxp3+ cells/10 high power fields (hpf) were counted (vs. mean 28/10 hpf, p<.05 in controls), suggesting that lower numbers of Tregs were also present in the bone marrow of AA patients. In conclusion, our results suggest that Tregs are decreased in blood and marrow of patients with idiopathic AA, consistent with the breach of peripheral tolerance in AA. In addition to flow cytometry, immunohistochemical staining of histologic specimens can be used for the quantitative analysis of Tregs in bone marrow failure syndromes and other immune-mediated conditions such as GvHD.

scholarly journals Brazilian Consensus Meeting on Pediatric Hematopoietic Stem Cell Transplantation for Acquired Aplastic Anemia and Inherited Bone Marrow Failure Syndromes

JBMTCT ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 151
Author(s):  
Luiz Guilherme Darrigo Junior ◽  
Gisele Loth ◽  
Phillip Scheinberg ◽  
Elias Hallack Atta ◽  
Carmem Bonfim
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Bone Marrow Failure ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACQUIRED APLASTIC ANEMIA AND INHERITED BONE MARROW FAILURE SYNDROMES

Effects of Rabbit Anti-Mouse Thymocyte Globulin Treatment in a Splenocyte-Induced Model of Aplastic Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1172-1172
Author(s):  
Melanie C Ruzek ◽  
Kathleen Phillips ◽  
Susan Richards ◽  
Khalid Mamlouk ◽  
John Williams ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Complete Response ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Mouse Thymocyte ◽  
Immune Mediated ◽  
Severe Pancytopenia ◽  
High Doses

Abstract Abstract 1172 Acquired aplastic anemia is an immune-mediated disease where destruction of hematopoietic stem cells (HSCs) in the bone marrow results in severe and life-threatening pancytopenia. Thymoglobulin® is often used as immunosuppressive therapy in this disease with up to 80 percent of patients responding to a combination of Thymoglobulin and cyclosporine. In an effort to better understand the activities and mechanism of action of Thymoglobulin we developed a mouse model of immune-mediated aplastic anemia and evaluated a murine surrogate of Thymoglobulin®, rabbit anti-mouse thymocyte globulin (mATG) in this model. We modified a graft-versus-host (GVH)-induced model described in the literature (Bloom, et al., 2004) utilizing HSC-depleted spleen cells transferred from C57BL/6 into CByB6F1 mice instead of lymph node cell transfer. Our modified model shows a cell dose-dependent increase in pancytopenia and lethality. Mice receiving a high dose (100×106) of HSC-depleted splenocytes experienced severe pancytopenia and rapid death occurring around day 21 whereas mice receiving lower doses (70×106, 35×106 and 17×106) of cells showed progressively less pancytopenia and lethality as the dose of cells decreased. Histopathology also showed marked loss of hematopoietic progenitor cells in the bone marrow with little evidence of GVHD in other tissues. Prophylactic administration of mATG (25mg/kg, 2x, day 0 and 3) to mice given high doses of HSC-depleted splenocytes (100×106) resulted in a significant improvement in pancytopenia and survival (70%) in this model. Interestingly, therapeutic administration of mATG was more effective when given later relative to disease induction. Delivery of mATG (25mg/kg, 2x, three days apart) starting on day 3 showed some delay in disease progression (day 30 vs day 21) and mATG started on day 6 slightly increased survival (40%). However, mice receiving mATG starting on days 10 or 14 showed a much greater overall survival of 100% and 60%, respectively, with full rebound of hematopoietic cells in the blood to normal levels. The complete response observed with later mATG administration (day 10 or day 14) mimics the treatment and response of patients given Thymoglobulin®. In summary, we have established a novel model of HSC-depleted splenocyte induction of bone marrow failure in mice that is responsive to therapeutic ATG administration. Studies in this model will aid in further understanding the mechanism of ATG in aplastic anemia and may contribute to the development of potential new therapies. Disclosures: Ruzek: Genzyme: Employment. Phillips:Genzyme: Employment. Richards:Genzyme: Employment. Mamlouk:Genzyme: Employment. Williams:Genzyme: Employment. Garman:Genzyme: Employment.

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