Association of Telomere Length in Dyskeratosis Congenita Lymphocytes with Increased Sensitivity to Radiation and Anti-Mitotic Agents.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2833-2833 ◽  
Author(s):  
Michael A. Beasley ◽  
Vibha Singhal ◽  
Aloysius J. Klingelhutz ◽  
Ike Akabogu ◽  
Frederick D. Goldman
Keyword(s):  
Bone Marrow Failure ◽  
Skin Pigmentation ◽  
Dyskeratosis Congenita ◽  
Premature Aging ◽  
Cytotoxic Agents ◽  
Cell Surface Expression ◽  
Cell Transplant ◽  
Telomere Shortening ◽  
Hematopoietic Stem ◽  
Increased Sensitivity

Abstract Dyskeratosis congenita (DC) is a premature aging syndrome characterized by progressive bone marrow failure, abnormal skin pigmentation and nail dystrophy. We have recently described an autosomal dominant form of DC (AD DC) in a large three-generation kindred that is due to a mutation in the gene encoding human telomerase RNA (hTR). Importantly, we have noted progressive shortening of telomeres in lymphocytes from the most recent generation, correlating with earlier onset of severe cytopenias in some of these patients. While telomere shortening is a normal consequence of the aging process, DC patients display accelerated telomere shortening in many somatic cell types. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy for marrow failure in DC. However, HSCT in DC is generally poorly tolerated and associated with significant morbidity, perhaps as a consequence of increased sensitivity of dividing cells to cytotoxic agents. To test this hypothesis, we characterized lymphocytes from nine AD DC patients and age matched controls that had been placed in long term culture following in vitro exposure to irradiation (137Cs) and varying doses of Taxol. Cell proliferation and viability were quantitated by direct visual counting on a hemocytometer, and flow cytometry was employed to assess apoptosis and cell surface expression of senescent markers. CD57 and CD95, markers of cellular senescence and apoptosis, were significantly upregulated on DC T lymphocytes after two weeks in culture relative to controls. In addition to DC lymphocytes having a decreased proliferative capacity, an increased sensitivity to Taxol was noted, with an average decrease of 21% in cell growth relative to similarly treated control cells. This effect was also noted in irradiated DC cells. Finally, DC lymphocytes displayed an increased apoptotic index in the presence of varying doses of Taxol. These results suggest that telomere shortening may be an important factor in determining cellular tolerance to cytotoxic therapy and support the concept of reduced intensity HSCT regimens in both aged individuals and DC patients.

The Role of Telomerase Activity and Telomere Length in Cellular Sensitivity to DNA Damaging Agents.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4192-4192
Author(s):  
Greg T. Rice ◽  
Michael A. Beasley ◽  
Ike I. Akabogu ◽  
Erik R. Westin ◽  
Dale A. Winnike ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Telomere Length ◽  
Bone Marrow Failure ◽  
Skin Pigmentation ◽  
Cytotoxic Agents ◽  
Cell Surface Expression ◽  
Cell Transplant ◽  
Telomere Shortening ◽  
Hematopoietic Stem ◽  
Increased Sensitivity

Abstract Dyskeratosis congenita (DC) is a premature aging syndrome characterized by progressive bone marrow failure, abnormal skin pigmentation and nail dystrophy. We have described an autosomal dominant form of DC (AD DC) in a large three-generation kindred that is due to a mutation in the gene encoding human telomerase RNA (hTR). While telomere shortening is a normal consequence of the aging process, DC patients display extremely short telomeres in many somatic cell types, including hematopoietic cells, and they often suffer from bone marrow failure. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy for marrow failure in DC. However, HSCT in DC is generally poorly tolerated and associated with significant morbidity, perhaps as a consequence of increased sensitivity of dividing cells to cytotoxic agents during myeloablative therapy. To test this hypothesis, we characterized lymphocytes from various AD DC patients and age matched controls that had been placed in long term culture following in vitro exposure to irradiation (137Cs) and varying doses of Taxol, Adriamycin, and Etoposide. Cell proliferation and viability were quantified by direct visual counting on a hemocytometer, and flow cytometry was employed to assess apoptosis and cell surface expression of senescent markers. In addition to DC lymphocytes having a decreased proliferative capacity and higher basal apoptotic levels, an increased sensitivity to irradiation, Taxol, Adriamycin, and Etoposide was noted. These results suggest that telomere shortening may be an important factor in determining cellular tolerance to cytotoxic therapy and support the concept of reduced intensity HSCT regimens in both aged individuals and DC patients. Further studies have been initiated to determine whether reconstitution of telomere length in DC cells alters response to cytotoxic agents.

Longitudinal Changes In Telomere Length In Patients with Dyskeratosis Congenita

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2230-2230
Author(s):  
Blanche P Alter ◽  
Neelam Giri ◽  
Peter M. Lansdorp ◽  
Gabriela M. Baerlocher ◽  
Philip S Rosenberg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Telomere Length ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Premature Aging ◽  
Bone Marrow Failure Syndrome ◽  
Cross Sectional ◽  
Telomere Shortening ◽  
Early Presentation ◽  
Telomere Attrition

Abstract Abstract 2230 Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome with a complex clinical phenotype, including dysplastic nails, lacy reticular pigmentation, and oral leukoplakia (the diagnostic triad). Numerous other physical abnormalities may be present, in addition to cytopenias due to bone marrow failure, and a high risk of leukemia or solid tumors. However, many patients have no physical findings at diagnosis. Patients with DC have very short telomeres, and approximately one-half have a mutation in one of six genes important in telomere biology. Telomere length in leukocyte subsets, measured by automated flow fluorescence in situ hybridization (flow-FISH), is both sensitive and specific for identifying individuals with DC. Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are critical in chromosomal stability which shorten during normal cell division. Cross-sectional studies of normal individuals suggest that telomere length decreases with age in a sigmoid pattern from birth to old age. In a cross-sectional analysis of 26 patients with DC, we previously observed that telomere length appeared to be stable or even to slightly increase with age (BP Alter et al, Blood 110:149, 2007). Similar results were shown in 23 different DC patients by others (M Bessler et al, FEBS Lett 2010 in press). We speculated that these data were influenced by early presentation (or recognition) of clinically more severe patients, while patients with similar telomere length who were clinically milder were identified at older ages. In this pilot study, we examined, for the first time, the longitudinal age-association of telomere attrition in nine patients with DC who were followed for five to seven years (currently 8 – 50 years of age). These include three patients with mutations in TERC, and two each with TINF2, TERT, and DKC1 mutations. When first studied, four had normal hematopoiesis, three moderate cytopenias, one was receiving androgens, and one was on transfusions. Subsequently, one with normal hematopoiesis developed mild thrombocytopenia, one who was on transfusions responded to androgens, and one with moderate aplastic anemia became severe. In all cases, telomere length decreased with age. In a linear regression model, the average annual decrease in telomere length in lymphocytes was 167 base pairs/year (bp/yr) + 104, similar to the rate in granulocytes, 159 + 92 bp/yr. According to the literature, the rate of telomere attrition in longitudinal studies in normal blood is ∼45-50 bp/yr, albeit by methods other than flow-FISH; the rate of telomere shortening appears to decrease with increasing age. The average patient Z-scores at the beginning of the study were -3.9 standard deviations below the median for age in healthy normal controls, and were -4.3 at the end, consistent with the impression that DC patient telomeres shorten somewhat more than expected from normal aging. These data support the hypothesis that the earlier cross-sectional results for patients with DC indeed were influenced by the cross-sectional rather than longitudinal nature of the data. The current longitudinal data suggest that telomere shortening could possibly be accelerated in patients with DC, but larger studies are required. Our results indicate that patients with DC have telomeres that are much shorter than normal for their age, and that over time they continue to shorten, consistent with DC being classified as a disorder of premature aging. Disclosures: Lansdorp: Repeat Diagnostics: Equity Ownership.

scholarly journals Telomere maintenance and human bone marrow failure

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4446-4455 ◽  
Author(s):  
Rodrigo T. Calado ◽  
Neal S. Young
Keyword(s):  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Genetic Diseases ◽  
Telomerase Activity ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance ◽  
Telomere Shortening ◽  
Hematopoietic Stem ◽  
Telomere Binding Protein ◽  
Genes Encoding

AbstractAcquired and congenital aplastic anemias recently have been linked molecularly and pathophysiologically by abnormal telomere maintenance. Telomeres are repeated nucleotide sequences that cap the ends of chromosomes and protect them from damage. Telomeres are eroded with cell division, but in hematopoietic stem cells, maintenance of their length is mediated by telomerase. Accelerated telomere shortening is virtually universal in dyskeratosis congenita, caused by mutations in genes encoding components of telomerase or telomere-binding protein (TERT, TERC, DKC1, NOP10, or TINF2). About one-third of patients with acquired aplastic anemia also have short telomeres, which in some cases associate with TERT or TERC mutations. These mutations cause low telomerase activity, accelerated telomere shortening, and diminished proliferative capacity of hematopoietic progenitors. As in other genetic diseases, additional environmental, genetic, and epigenetic modifiers must contribute to telomere erosion and ultimately to disease phenotype. Short telomeres also may cause genomic instability and malignant progression in these marrow failure syndromes. Identification of short telomeres has potential clinical implications: it may be useful in dyskeratosis congenita diagnosis, in suggesting mutations in patients with acquired aplastic anemia, and for selection of suitable hematopoietic stem cell family donors for transplantation in telomerase-deficient patients.

Association of immune abnormalities with telomere shortening in autosomal-dominant dyskeratosis congenita

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 682-688 ◽  
Author(s):  
Matt Knudson ◽  
Shashikant Kulkarni ◽  
Zuhair K. Ballas ◽  
Monica Bessler ◽  
Frederick Goldman
Keyword(s):  
Autosomal Dominant ◽  
Bone Marrow Failure ◽  
Skin Pigmentation ◽  
Cell Number ◽  
Dyskeratosis Congenita ◽  
Immunoglobulin M ◽  
Dominant Form ◽  
Telomere Shortening

Abstract Dyskeratosis congenita (DC) is an inherited bone marrow failure disorder characterized by abnormal skin pigmentation and nail dystrophy. We have recently described, in 10 members of a large 3-generation family, an autosomal-dominant form of DC (AD DC) that is due to a mutation in the gene-encoding human telomerase RNA (TERC), resulting in telomere shortening. In studying the immunologic consequences of TERC mutations, severe B lymphopenia and decreased immunoglobulin M (IgM) levels were noted. T cells were found to overexpress senescent markers, including CD57 and Fas receptor, and were moderately reduced in cell number. To determine whether these in vivo findings were related to cellular replicative defects, short-term cultures of AD DC lymphocytes were established to measure proliferation, mitoses, and apoptosis. AD DC lymphocytes displayed a markedly reduced proliferative capacity and increased basal apoptotic rate. Finally, telomere shortening was most prominent in third-generation subjects, and there appeared to be a correlation between telomere length and in vivo and in vitro immune findings. In summary, the observed lymphopenia and hypogammaglobulinemia in AD DC is likely a consequence of replicative failure and premature senescence of lymphocytes, supporting a role of telomerase activity in immune homeostasis.

scholarly journals Zebrafish Models Provide Novel Insights into the Disease Biology of Parn-Mutant Dyskeratosis Congenita and DNAJC21-Mutant Shwachman-Diamond Syndrome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1110-1110
Author(s):  
Sarada Ketharnathan ◽  
Sergey Prykhozhij ◽  
Anna Cordeiro ◽  
Yigal Dror ◽  
Jason N Berman
Keyword(s):  
Lipid Metabolism ◽  
Genetic Manipulation ◽  
Fetal Liver ◽  
Bone Marrow Failure ◽  
Skin Pigmentation ◽  
Larval Growth ◽  
Dyskeratosis Congenita ◽  
Cell Transplant ◽  
Dependent Manner ◽  
Shwachman Diamond Syndrome

Abstract Inherited bone marrow failure syndromes (IBMFS) are a group of rare inherited genetic disorders defined by impaired hematopoiesis and multi- or unilineage cytopenias. Dyskeratosis Congenita (DC) is characterized by pancytopenia, abnormal skin pigmentation and leukoplakia and is caused by mutations in genes involved in telomere biogenesis and/or RNA processing such as TERT, TERC, DKC1 and PARN. Shwachman-Diamond syndrome (SDS) is characterized by neutropenia and exocrine pancreatic insufficiency and occurs as a result of mutations in genes required for ribosome subunit maturation such as SBDS, DNAJC21 and EFL1. How the disruption of such ubiquitous cellular processes leads to distinct cytopenic phenotypes is not fully understood. Further, IBMFS patients have a high risk of developing myelodysplastic syndrome and/or acute myeloid leukemia with a cumulative incidence of 36% by 30 years of age for SDS patients and 13% for DC patients who do not undergo a stem cell transplant. As IBMFS are rare and large numbers of primary human samples are not readily available for mechanistic studies, we employed zebrafish (Danio rerio) given their highly conserved hematopoietic program and ease of genetic manipulation. Using CRISPR-Cas9 genomic editing, we generated deletion mutations predicted to introduce premature stop codons in the zebrafish orthologs, parn and dnajc21, two more recently identified causes of DC and SDS, respectively. Homozygous zygotic parn mutants had normal morphology and were viable to adulthood. However, fertile homozygous adult females were not recoverable in subsequent generations, implicating parn as an essential factor in oocyte specification. In contrast, homozygous dnajc21 mutants showed normal development to adulthood. Using whole mount in situ hybridization (WISH), we found increased expression of hematopoietic precursor markers (erythroid - gata1 and myeloid - lcp1) and concurrently decreased expression of mature hematopoietic markers (erythroid - hbbe3, myeloid - mpx and thrombocyte - CD41) in parn mutants at 24- and 48-hours post-fertilization (hpf). Further, o-dianisidine staining showed reduced hemoglobinized erythrocytes at 48 hpf. These data indicate that multilineage embryonic hematopoiesis is compromised in parn mutants, recapitulating the pancytopenia observed in patients with DC. WISH for mpx in dnajc21 mutants revealed reduced expression at 24 and 48 hpf, recapitulating the neutropenia seen in SDS. Activation of the TP53 tumor suppressor pathway has been suggested to mediate marrow failure and leukemic progression in some types of IBMFS. Using quantitative PCR to measure the expression of tp53 and its downstream effector p21 at 48 hpf, we observed no significant changes in parn mutants but significantly upregulated tp53 expression in dnajc21 mutants. To further study the role of tp53 in dnajc21-mutant SDS, we crossed dnajc21 mutants with a zebrafish line carrying a tp53 R217H point mutation that confers anti-apoptotic phenotypes. Heterozygous tp53 loss in a dnajc21-/- or +/- background resulted in reduced overall larval growth and abnormal yolk sac development, suggesting defective lipid metabolism. Using the lipophilic dye, Oil Red O, we observed reduced lipid distribution in the vasculature and caudal hematopoietic tissue region (equivalent to mammalian fetal liver) of dnajc21 mutants at 48 hpf. In summary, these findings support a role for PARN in hematopoietic lineage specification through mechanisms that are predominantly TP53-independent. By contrast, DNAJC21 is required for neutrophil specification and normal lipid metabolism and may function in a TP53-dependent manner. These zebrafish models provide new insights into the unique biology underlying these IBMFS and can serve as an in vivo platform for identifying therapeutic compounds that restore normal hematopoiesis and prevent leukemic transformation. Disclosures Dror: Alexion Canada: Other: Received funding for a Marrow Failure and Myelodysplasia conference that I organized April 2021; RepaetDiagnostic Laboratory: Other: Received funding for a Marrow Failure and Myelodysplasia conference that I organized April 2021. Berman: Oxford Immune Algorithmics: Membership on an entity's Board of Directors or advisory committees.

Inherited Failure Syndromes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-10-SCI-10
Author(s):  
Grover C. Bagby
Keyword(s):  
Relative Risk ◽  
Diagnostic Tests ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Genetic Diagnosis ◽  
Hematopoietic Cells ◽  
Dyskeratosis Congenita ◽  
Inherited Disorders ◽  
Hematopoietic Stem ◽  
Diagnostic Certainty

Abstract Abstract SCI-10 Global and lineage-restricted bone marrow failure syndromes can be acquired or inherited. Each of the known inherited disorders was initially described by observant clinicians before the field had access to modern tools of molecular biology and genetics. Consequently until recently, diagnosis had depended entirely on a clinical context drawn from the medical and family history, careful physical examinations and a few laboratory tests, none of which were pathognomonic. Today, many of the mutated genes responsible for these phenotypes have been identified and diagnostic tests of good reliability are emerging. This presentation will review the advantages and pitfalls associated with the application of newer diagnostic tests for many of these diseases. The molecular genetic insights have provided additional clinically relevant lessons. For example, the diseases are not limited to patients with the “classic” phenotype and can be diagnosed initially in adulthood. A substantial fraction of patients with Fanconi anemia (FA), for example, does not exhibit the cutaneous or skeletal manifestations of the disease. Some FA patients have entirely normal hematopoiesis, including the responses of hematopoietic cells to mitomycin C or diepoxybutane (abnormalities of which are considered to be the diagnostic standard for this disease). Such patients are “mosaics” in which a single hematopoietic stem cell has corrected the defect on one mutant FA allele and gives it and its progeny such a competitive advantage that they repopulate the entire marrow. Establishing the diagnosis in such cases is essential because the patients remain at high risk for squamous cell carcinoma and because their non-hematopoietic cells remain hypersensitive to cross-linking agents. Between these syndromes there are some shared genetic dysfunctions. For example, cells from patients with dyskeratosis congenita, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia have genetic lesions that directly perturb ribosome biogenesis. Few of these disorders are caused by the inactivation of only one gene. There are at least 13 FA genes, more than 6 dyskeratosis congenita genes, more than one Shwachman-Diamond gene, more than 6 Diamond-Blackfan genes, and at least 7 genes for congenital neutropenia. Not surprisingly, some of these genes encode mutually interacting proteins (the most widely studied of these form a nuclear Fanconi interactome). While the identification of involved genes has advanced our levels of diagnostic certainty, the discoveries have posed many challenges and the list of unanswered questions is growing longer. The most cost-effective approaches to diagnosis are not perfectly defined and although mutation analysis is of profound research importance and required for certain management strategies (e.g. in vitro fertilization and pre-implantation genetic diagnosis) the clinical value of assigning patients to specific complementation groups or mutations has not yet been clearly demonstrated. Leading research questions for hematologists focusing on these disorders include: How do these disparate genetic lesions influence the function of hematopoietic stem cells so profoundly? What environmental influences play a role in marrow failure progression and do the mutant gene products interact biochemically with signals evolving from environmental cues? What accounts for the high relative-risk of myelodysplasia and acute leukemia in all of these disorders? Will effective gene therapy reduce the relative risk of MDS and AML? Hypotheses centering on each of these points are now being tested in a number of laboratories and some of them will be summarized in this presentation. Disclosures No relevant conflicts of interest to declare.

Screening Patients with Myelodysplastic Syndrome and Aplastic Anemia for Paroxysmal Nocturnal Hemoglobinuria Clones: A Retrospective Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3426-3426 ◽  
Author(s):  
Andrew Shih ◽  
Ian H. Chin-Yee ◽  
Ben Hedley ◽  
Mike Keeney ◽  
Richard A. Wells ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retrospective Study ◽  
Aplastic Anemia ◽  
Board Of Directors ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Cell Surface Expression ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Pnh Clone

Abstract Abstract 3426 Introduction: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare disorder due to a somatic mutation in the hematopoietic stem cell. The introduction of highly sensitive flow cytometric and aerolysin testing have shown the presence of PNH clones in patients with a variety of other hematological disorders such as aplastic anemia (AA) and myelodysplasic syndrome (MDS). It is hypothesized that patients with these disorders and PNH clones may share an immunologic basis for marrow failure with relative protection of the PNH clone, due to their lack of cell surface expression of immune accessory proteins. This is supported by the literature showing responsiveness in AA and MDS to immunosuppressive treatments. Preliminary results from a recent multicenter trial, EXPLORE, notes that PNH clones can be seen in 70% of AA and 55% of MDS patients, and therefore there may be utility in the general screening of all patients with bone marrow failure (BMF) syndromes. Furthermore, it has been suggested that the presence of PNH cells in MDS is a predictive biomarker that is clinically important for response to immunosuppressive therapy. Methods: Our retrospective cohort study in a tertiary care center used a high sensitivity RBC and FLAER assay to detect PNH clones as small as 0.01%. Of all patients screened with this method, those with bone marrow biopsy and aspirate proven MDS, AA, or other BMF syndromes (defined as unexplained cytopenias) were analysed. Results from PNH assays were compared to other clinical and laboratory parameters such as LDH. Results: Overall, 102 patients were initially screened over a 12 month period at our center. 30 patients were excluded as they did not have biopsy or aspirate proven MDS, AA, or other BMF syndromes. Of the remaining 72 patients, four patients were found to have PNH clones, where 2/51 had MDS (both RCMD, IPSS 0) [3.92%] and 2/4 had AA [50%]. The PNH clone sizes of these four patients were 0.01%, 0.01%, 0.02%, and 1.7%. None of the MDS patients with known recurrent karyotypic abnormalities had PNH clones present. Only one of the four patients had a markedly increased serum LDH level. Conclusions: Our retrospective study indicates much lower incidence of PNH clones in MDS patients or any patients with BMF syndromes when compared to the preliminary data from the EXPLORE trial. There is also significant disagreement in other smaller cohorts in regards to the incidence of PNH in AA and MDS. Screening for PNH clones in patients with bone marrow failure needs further study before adoption of widespread use. Disclosures: Keeney: Alexion Pharmaceuticals Canada Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wells:Alexion Pharmaceuticals Canada Inc: Honoraria. Sutherland:Alexion Pharmaceuticals Canada Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Excelent Option Therapy of BONE Marrow Failure in Fanconi Anemia Patients Withouth Full Match Donnor

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5075-5075 ◽  
Author(s):  
Lisandro L Ribeiro ◽  
Samantha Nichele ◽  
marco Antonio Bitencourt ◽  
Ricardo Petterle ◽  
Gisele Loth ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Hematological Parameters ◽  
Severe Neutropenia ◽  
Cell Transplant ◽  
Variable Degree ◽  
Duration Of Treatment ◽  
Hematopoietic Stem ◽  
Hematological Response

Abstract The main cause of morbidity and mortality of FA pts is bone marrow failure (BMF), which usually arises in the first decade of life and progresses to transfusion dependence and severe neutropenia. Androgen treatment has been recommended for FA pts with BMF for whom there is no acceptable hematopoietic stem cell transplant donor. Oxymetholone and Danazol are frequently used in these pts. We retrospectively analyzed data on 67 FA pts who received oxymetholone or danazol for the treatment of their BMF. The starting dose was approximately 1mg/kg for oxy and 2-4mg/kg for danazol. The hematological parameters at the initiation of treatment were hemoglobin (Hb) < 8 g/dL and/or thrombocytes < 30.000/μl. Patients were diagnosed between 01.2005 and 01.2016. The median age was 10.5 ys (2.9 - 40ys). Gender: 39M/27F. The median duration of treatment was 18m (3m - 95m). Fifty-three patients (79%) showed hematological response and became transfusion independence at a median of 3 months after beginning oxymetholone (2-9m) and 5 months after danazol (4-7m). Two adult pts treated with danazol achieved total hematological response with 2.5mg/kg. Seven pts are stable after tapering and stopping androgen with a median follow up of 4 ys (6m-8.5ys). Fourteen pts did not respond to treatment (21%). Eleven pts received an HSCT and seven are alive and well. Three pts were not transplanted and two are alive but transfusion dependent and one pt died from CNS bleeding. All patients developed variable degree of virilization but it was more evident with oxymetholone therapy. Older age at starting therapy was related to less virilization. Conclusion: This study shows the largest number of FA pts treated with androgen up till now. Androgen is an effective and well-tolerated treatment option for FA pts who develop BMF with 79% of them showing transfusion free after 3-5 months. This response may give us time to search for better donors. Disclosures No relevant conflicts of interest to declare.

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