scholarly journals How I treat Diamond-Blackfan anemia

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3715-3723 ◽  
Author(s):  
Adrianna Vlachos ◽  
Ellen Muir
Keyword(s):  
Molecular Mechanisms ◽  
Bone Marrow Failure ◽  
Large Subunit ◽  
Clinical Manifestations ◽  
Iron Chelation ◽  
Clinical Findings ◽  
Patient Registries ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem ◽  
Diamond Blackfan Anemia

Abstract Diamond-Blackfan anemia (DBA) is characterized by red cell failure, the presence of congenital anomalies, and cancer predisposition. In addition to being an inherited bone marrow failure syndrome, DBA is also categorized as a ribosomopathy as, in more than 50% of cases, the syndrome appears to result from haploinsufficiency of either a small or large subunit-associated ribosomal protein. Nonetheless, the exact mechanism by which haploinsufficiency results in erythroid failure, as well as the other clinical manifestations, remains uncertain. New knowledge regarding genetic and molecular mechanisms combined with robust clinical data from several international patient registries has provided important insights into the diagnosis of DBA and may, in the future, provide new treatments as well. Diagnostic criteria have been expanded to include patients with little or no clinical findings. Patient management is therefore centered on accurate diagnosis, appropriate use of transfusions and iron chelation, corticosteroids, hematopoietic stem cell transplantation, and a coordinated multidisciplinary approach to these complex patients.

scholarly journals Generation of Dyskeratosis Congenita-like Hematopoietic Stem Cells through the Stable Inhibition of DKC1

2021 ◽  
Author(s):  
Carlos Carrascoso-Rubio ◽  
Hidde A. Zittersteijn ◽  
Laura Pintado-Berninches ◽  
Beatriz Fernández-Varas ◽  
M. Luz Lozano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Dyskeratosis Congenita ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Cd34 Cells

Abstract Dyskeratosis congenita (DC) is a rare telomere biology disorder, which results in different clinical manifestations, including severe bone marrow failure. To date, the only curative treatment for bone marrow failure in DC patients is allogeneic hematopoietic stem cell transplantation. However due to the toxicity associated to this treatment, improved therapies are recommended for DC patients. Here we aimed at generating DC-like human hematopoietic stem cells in which the efficacy of innovative therapies could be investigated. Because X-linked DC is the most frequent form of the disease and is associated with an impaired expression of DKC1, we have generated DC-like hematopoietic stem cells based on the stable knock-down of DKC1 in human CD34 + cells with lentiviral vectors encoding for DKC1 short hairpin RNAs. At a molecular level, DKC1 -interfered CD34 + cells showed a decreased expression of TERC, as well as a diminished telomerase activity and increased DNA damage, cell senescence and apoptosis. Moreover, DKC1 -interfered human CD34 + cells showed defective clonogenic ability and were incapable of repopulating the hematopoiesis of immunodeficient NSG mice. The development of DC-like hematopoietic stem cells will facilitate the understanding of the molecular and cellular basis of this inherited bone marrow failure syndrome, and will serve as a platform to evaluate the efficacy of new hematopoietic therapies for DC.

Diamond-Blackfan Anemia: Erythropoiesis Lost in Ribosome Biosynthesis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-2-SCI-2
Author(s):  
Stefan Karlsson ◽  
Johan Flygare ◽  
Pekka Jaako ◽  
David Bryder
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Macrocytic Anemia ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Diamond Blackfan Anemia

Abstract Abstract SCI-2 Diamond-Blackfan anemia (DBA) is a rare congenital erythroid hypoplasia that presents early in infancy. The classic hematologic profile of DBA consists of macrocytic anemia with selective absence of erythroid precursors in a normocellular bone marrow, normal or slightly decreased neutrophil, and variable platelet count. During the course of the disease some patients show decreased bone marrow cellularity that often correlates with neutropenia and thrombocytopenia. DBA is a developmental disease since almost 50% of the patients show a broad spectrum of physical abnormalities. All known DBA disease genes encode for ribosomal proteins that collectively explain the genetic basis for approximately 55% of DBA cases. Twenty-five percent of the patients have mutations in a gene encoding for ribosomal protein S19 (RPS19). All patients are heterozygous with respect to RPS19 mutations suggesting a functional haploinsufficiency of RPS19 as basis for disease pathology. Despite the recent advances in DBA genetics, the pathophysiology of the disease remains elusive. Cellular studies on patients together with successful marrow transplantation have demonstrated the intrinsic nature of the hematopoietic defect. DBA patients have a variable deficit in burst-forming unit-erythroid (BFU-E) and colony-forming unit-erythroid (CFU-E) progenitors. The frequency of immature hematopoietic progenitors in DBA patients is normal but their proliferation is impaired in vitro. Generation of animal models for RPS19-deficient DBA is pivotal to understand the disease mechanisms and to evaluate novel therapies. Several DBA models have been generated in mice or zebrafish. Although these models have provided important insights on DBA, they are limited in a sense that the hematopoietic phenotype and molecular mechanisms are likely to be influenced by the level of RPS19 downregulation. We have generated mouse models for RPS19-deficient DBA by taking advantage of transgenic RNAi. These models are engineered to contain a doxycycline-regulatable RPS19-targeting shRNA, allowing a reversible and dose-dependent downregulation of RPS19 expression. We demonstrate that the RPS19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count and the severity of the phenotype depends on the level of RPS19 downregulation. We show further that a chronic RPS19 deficiency leads to irreversible exhaustion of hematopoietic stem cells and subsequent bone marrow failure. Overexpression of RPS19 following gene transfer rescues the proliferative and apoptotic phenotype of RPS19-deficient hematopoietic progenitors in vitro, demonstrating that the phenotype is specifically caused by the RPS19 deficiency. Expression analysis of RPS19-deficient hematopoietic progenitors reveals an activation of the p53 pathway. By intercrossing the DBA mice with p53 null mice we demonstrate that inactivation of p53 in vivo results in a variable rescue of the hematopoietic phenotype depending on the level of RPS19 downregulation. Therefore, we conclude that increased activity of p53 plays a major role in causing the DBA phenotype but that other hitherto unidentified pathways also play a role, specifically in patients that have low levels of functional RPS19. Disclosures: No relevant conflicts of interest to declare.

Enhanced NF-Kb Non-Canonical Signaling Impairs Hematopoietic Stem Cell Self-Renewal

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2367-2367
Author(s):  
Yan Xiu ◽  
Chen Zhao
Keyword(s):  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Critical Role ◽  
Wild Type ◽  
Bone Marrow Failure Syndrome ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Marrow Cellularity ◽  
Mutant Cells

Abstract We previously demonstrated that the NF-B non-canonical signaling way positively and intrinsically regulates hematopoietic stem/progenitor cell (HSPC) self-renewal and maintains stromal/osteoblastic niches (Stem Cells 2012 30:709-18). These results lead us to think that persistent activation of NF-B non-canonical signaling would have favorable effects on the HSPC pool size and self-renewal capacity. NF-B-inducing kinase (NIK) plays a critical role in non-canonical NF-B signaling by directly phosphorylating IKK. It is constitutively degraded by TRAF3 in unstimulated cells to prevent unwanted NF-B activation. To investigate the enhanced NF-kB non-canonical signaling specifically in hematopoietic cells, we crossed Vav-Cre mice with a mouse strain in which a mutated form of NIK lacking the TRAF3-binding domain is expressed under the control of the ROSA26 promoter after Cre-mediated deletion of the LoxP-flanked STOP cassette (NIKΔT3Cre mice). In contrast to what we expected in these preliminary studies, the NIKΔT3Cre mice rapidly developed anemia, pancytopenia, with a reduced HSPC pool and marrow cellularity and postnatal lethality, mimicking many of the findings in humans with bone marrow failure syndrome, and different from recently published mice with deficiency in A20, which also activates NF-B signaling. Furthermore, the NIK activated HSPCs have profoundly impaired engraftment and self-renewal activity after transplantation into wild-type recipients. Further analysis showed that the mutant cells are proliferate faster and predispose to apoptosis than wild type cells. These observations suggest that finely controlled NF-B activity is crucial for HSC maintenance. Currently, we are focusing on the analysis of the underlying molecular mechanisms. Disclosures No relevant conflicts of interest to declare.

scholarly journals Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Carlos Carrascoso-Rubio ◽  
Hidde A. Zittersteijn ◽  
Laura Pintado-Berninches ◽  
Beatriz Fernández-Varas ◽  
M. Luz Lozano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Dyskeratosis Congenita ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Telomere Biology

AbstractDyskeratosis congenita (DC) is a rare telomere biology disorder, which results in different clinical manifestations, including severe bone marrow failure. To date, the only curative treatment for the bone marrow failure in DC patients is allogeneic hematopoietic stem cell transplantation. However, due to the toxicity associated to this treatment, improved therapies are recommended for DC patients. Here, we aimed at generating DC-like human hematopoietic stem cells in which the efficacy of innovative therapies could be investigated. Because X-linked DC is the most frequent form of the disease and is associated with an impaired expression of DKC1, we have generated DC-like hematopoietic stem cells based on the stable knock-down of DKC1 in human CD34+ cells with lentiviral vectors encoding for DKC1 short hairpin RNAs. At a molecular level, DKC1-interfered CD34+ cells showed a decreased expression of TERC, as well as a diminished telomerase activity and increased DNA damage, cell senescence, and apoptosis. Moreover, DKC1-interfered human CD34+ cells showed defective clonogenic ability and were incapable of repopulating the hematopoiesis of immunodeficient NSG mice. The development of DC-like hematopoietic stem cells will facilitate the understanding of the molecular and cellular basis of this inherited bone marrow failure syndrome and will serve as a platform to evaluate the efficacy of new hematopoietic therapies for DC.

scholarly journals Generation of Dyskeratosis Congenita-like Hematopoietic Stem Cells through the Stable Inhibition of DKC1

2020 ◽  
Author(s):  
Carlos Carrascoso-Rubio ◽  
Hidde A. Zittersteijn ◽  
Laura Pintado-Berninches ◽  
Beatriz Fernández-Varas ◽  
M. Luz Lozano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Dyskeratosis Congenita ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Telomere Biology

Abstract Dyskeratosis congenita (DC) is a rare telomere biology disorder, which results in different clinical manifestations, including severe bone marrow failure. To date, the only curative treatment for bone marrow failure in DC patients is allogeneic hematopoietic stem cell transplantation. However due to the toxicity associated to this treatment, improved therapies are recommended for DC patients. Here we aimed at generating DC-like human hematopoietic stem cells in which the efficacy of innovative therapies could be investigated. Because X-linked DC is the most frequent form of the disease and is associated with an impaired expression of DKC1, we have generated DC-like hematopoietic stem cells based on the stable knock-down of DKC1 in human CD34+ cells with lentiviral vectors encoding for DKC1 short hairpin RNAs. At a molecular level, DKC1-interfered CD34+ cells showed a decreased expression of TERC, as well as a diminished telomerase activity and increased DNA damage, cell senescence and apoptosis. Moreover, DKC1-interfered human CD34+ cells showed defective clonogenic ability and were incapable of repopulating the hematopoiesis of immunodeficient NSG mice. The development of DC-like hematopoietic stem cells will facilitate the understanding of the molecular and cellular basis of this inherited bone marrow failure syndrome, and will serve as a platform to evaluate the efficacy of new hematopoietic therapies for DC.

scholarly journals Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia

Blood ◽  
2011 ◽  
Vol 118 (23) ◽  
pp. 6087-6096 ◽  
Author(s):  
Pekka Jaako ◽  
Johan Flygare ◽  
Karin Olsson ◽  
Ronan Quere ◽  
Mats Ehinger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Rna Interference ◽  
Ribosomal Protein ◽  
Mouse Models ◽  
Bone Marrow Failure ◽  
Macrocytic Anemia ◽  
Down Regulation ◽  
Hematopoietic Stem ◽  
Diamond Blackfan Anemia ◽  
Ribosomal Protein S19

Abstract Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging because the phenotype is highly dependent on the level of RPS19 down-regulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded down-regulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies. This study demonstrates the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene.

Genetics of Pediatric Immune-Mediated Diseases and Human Immunity

2021 ◽  
Vol 39 (1) ◽  
Author(s):  
Erica G. Schmitt ◽  
Megan A. Cooper
Keyword(s):  
Primary Immunodeficiency ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Annual Review ◽  
Publication Date ◽  
Hematopoietic Stem ◽  
Genetic Mechanisms ◽  
Human Immune Response ◽  
Genetically Determined ◽  
Complex Signaling

Primary immunodeficiency diseases (PIDs) are a rapidly growing, heterogeneous group of genetically determined diseases characterized by defects in the immune system. While individually rare, collectively PIDs affect between 1/1,000 and 1/5,000 people worldwide. The clinical manifestations of PIDs vary from susceptibility to infections to autoimmunity and bone marrow failure. Our understanding of the human immune response has advanced by investigation and discovery of genetic mechanisms of PIDs. Studying patients with isolated genetic variants in proteins that participate in complex signaling pathways has led to an enhanced understanding of host response to infection, and mechanisms of autoimmunity and autoinflammation. Identifying genetic mechanisms of PIDs not only furthers immunological knowledge but also benefits patients by dictating targeted therapies or hematopoietic stem cell transplantation. Here, we highlight several of these areas in the field of primary immunodeficiency, with a focus on the most recent advances. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Anesthetic Management of a Patient With Fanconi Anemia

2019 ◽  
Vol 66 (4) ◽  
pp. 218-220
Author(s):  
Saki Nagano ◽  
Masanori Tsukamoto ◽  
Takeshi Yokoyama
Keyword(s):  
Fanconi Anemia ◽  
Platelet Transfusion ◽  
Autosomal Recessive ◽  
Dental Treatment ◽  
Bone Marrow Failure ◽  
Anesthetic Management ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem ◽  
Dental Surgery ◽  
Preoperative Examination

Fanconi anemia (FA) is a type of bone marrow failure syndrome based on an autosomal recessive inherited trait with increased predisposition for other cancers. It is extremely rare and is characterized by short stature, polydactyly, and pancytopenia. At present, the only effective treatment for FA is allogeneic hematopoietic stem cell transplantation (SCT). Chemotherapy is necessary prior to allogeneic SCT. Dental treatment is usually performed before chemotherapy to reduce potential infections. We experienced the anesthetic management of a 4-year-old boy diagnosed with FA, who underwent extensive dental extractions before chemotherapy for SCT. In the preoperative examination, the platelet count was decreased to less than 3.0 × 104 cells/μL because of chronic pancytopenia. The patient received 20 units of platelet transfusion over 3 days prior to anesthesia. Dental surgery and multiple dental extractions were successfully completed under general anesthesia with sevoflurane, fentanyl, and remifentanil, and chemotherapy started 3 days postoperatively.

scholarly journals Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

2019 ◽  
Vol 48 (2) ◽  
pp. 770-787 ◽  
Author(s):  
Marco Lezzerini ◽  
Marianna Penzo ◽  
Marie-Françoise O’Donohue ◽  
Carolina Marques dos Santos Vieira ◽  
Manon Saby ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Missense Variant ◽  
Ribosomal Protein Gene ◽  
Multiple Cancer ◽  
Bone Marrow Failure Syndrome ◽  
Diamond Blackfan Anemia ◽  
Downstream Effects ◽  
Variant Analysis

Abstract Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5′UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5′UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5′UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.

Clonal Hematopoiesis in Patients with Diamond Blackfan Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Michelle Nash ◽  
Adrianna Vlachos ◽  
Marcin W. Wlodarski ◽  
Jeffrey Michael Lipton
Keyword(s):  
General Population ◽  
Myelodysplastic Syndrome ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Age Of Onset ◽  
Bone Marrow Failure ◽  
Large Subunit ◽  
Diamond Blackfan Anemia ◽  
Clonal Hematopoiesis

Background: Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by anemia, congenital anomalies and a predisposition to cancer. Patients usually present during infancy or early childhood, but can also be diagnosed as adults. In the vast majority of cases DBA is due to a mutation in a gene encoding a small or large subunit-associated ribosomal protein (RP) leading to RP haploinsufficiency. In a study of 702 patients enrolled in the DBA Registry (DBAR), the observed to expected ratio for acute myeloid leukemia (AML) was 28.8 and for myelodysplastic syndrome (MDS), 352.1 (Vlachos et al, Blood, 2018). The average age of onset for MDS in the DBA cohort was 26 years, compared to 60-70 years in the general population. Evolving clonal hematopoiesis (CH) with age has been observed as a precursor to MDS, with CH rarely observed in individuals younger than 40 years of age. Thus we hypothesized that the young age at the development of MDS in DBA would be presaged by evolving CH. Objective: The primary objective was to perform whole exome sequencing (WES) specifically screening for previously reported somatic mutations in 56 genes associated with CH (Jaiswal et al, NEJM, 2014). Design/Method: A total of 69 samples were analyzed from 65 patients, mostly targeting patients older than 18 years (median age 30 years). Multiple samples were run on patients who had available samples in the DBAR Biorepository to determine rate of acquisition of mutations. 468 age- and sex-matched healthy controls were made available from GeneDx who performed the WES for the study. We used a threshold for variant calling of minimum 5% with a minimum of 2 variant reads. Results: Three of the 65 DBA patients (5%) were found to have somatic mutations in STAG1, U2AF1, SF3B1, and DNMT3A at 8, 20, 41, and 70 years, respectively (Table 1). The patient who was 20 years of age had a sample in the DBAR biorepository from when he was age 8 years which was found to have a different somatic mutation (STAG1) than was found at present (U2AF1). This patient did go on to develop MDS at the age of 21 years. In comparison, of the 468 controls, 4 (0.8 %) had a somatic mutation in SF3B1, LUC7L2, DNMT3A, and LUC7L2 at ages 12, 31, 33 and 40 years, respectively. Conclusion: Patients with DBA show more somatic mutations as compared to controls (p<0.05). This early acquisition of mutations may be the driving force for their developing MDS at an earlier age than that of the general population. Further studies with more sensitive methods are warranted to accurately determine the prevalence of somatic CH mutations and their potential association with the development of myelodysplastic syndrome in these patients. Disclosures No relevant conflicts of interest to declare.

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