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Proceedings of the National Academy of... Nov 1997In recent years, there have been a number of technological breakthroughs that have allowed for clinical trials in gene therapy to be initiated. In combination with the... (Review)
Review
In recent years, there have been a number of technological breakthroughs that have allowed for clinical trials in gene therapy to be initiated. In combination with the genome initiative, the potential for new therapeutics is limitless. Although an enormous amount of information has been obtained in a relatively short period of time, gene therapy is not yet ready for wide-scale practice. Some of the successes and obstacles that remain are summarized in this report.
Topics: Bone Marrow Diseases; Genetic Therapy; Genetic Vectors; Humans; Liposomes; Viruses
PubMed: 9398067
DOI: 10.1073/pnas.94.24.12744 -
Molecular Therapy : the Journal of the... Dec 2015The combination of epigenetic reprogramming with advanced genome editing technologies opened a new avenue to study disease mechanisms, particularly of disorders with... (Review)
Review
The combination of epigenetic reprogramming with advanced genome editing technologies opened a new avenue to study disease mechanisms, particularly of disorders with depleted target tissue. Bone marrow failure syndromes (BMFS) typically present with a marked reduction of peripheral blood cells due to a destroyed or dysfunctional bone marrow compartment. Somatic and germline mutations have been etiologically linked to many cases of BMFS. However, without the ability to study primary patient material, the exact pathogenesis for many entities remained fragmentary. Capturing the pathological genotype in induced pluripotent stem cells (iPSCs) allows studying potential developmental defects leading to a particular phenotype. The lack of hematopoietic stem and progenitor cells in these patients can also be overcome by differentiating patient-derived iPSCs into hematopoietic lineages. With fast growing genome editing techniques, such as CRISPR/Cas9, correction of disease-causing mutations in iPSCs or introduction of mutations in cells from healthy individuals enable comparative studies that may identify other genetic or epigenetic events contributing to a specific disease phenotype. In this review, we present recent progresses in disease modeling of inherited and acquired BMFS using reprogramming and genome editing techniques. We also discuss the challenges and potential shortcomings of iPSC-based models for hematological diseases.
Topics: Anemia, Aplastic; Animals; Bone Marrow Diseases; Bone Marrow Failure Disorders; Disease Models, Animal; Epigenesis, Genetic; Genetic Engineering; Genetic Therapy; Hemoglobinuria, Paroxysmal; Humans; Induced Pluripotent Stem Cells
PubMed: 26435409
DOI: 10.1038/mt.2015.180 -
Environmental Health Perspectives Jun 1981Hematopoietic system toxicity is a major limiting factor in the use of aggressive combined modality therapy in the treatment of malignant disease. In this review, the... (Review)
Review
Hematopoietic system toxicity is a major limiting factor in the use of aggressive combined modality therapy in the treatment of malignant disease. In this review, the known drug-x-ray interactions using tissue culture systems are extended to the bone marrow compartment. Two hypotheses prevail for late bone marrow failure: (1) stromal damage to the vasculature with subsequent fibrosis and (2) irreversible stem cell depletion in the irradiated site. Clinical extensions of the experimental data for bone marrow kinetics in the animal model have not proven successful to date. The future strategies for therapy of malignancies in which both radiation and chemotherapy are employed may require dose modification or treatment planning to limit bone marrow toxicity.
Topics: Animals; Bone Marrow; Bone Marrow Diseases; Humans; Physical Phenomena; Physics; Radiation Injuries, Experimental
PubMed: 7016523
DOI: 10.1289/ehp.813959 -
Mutation Research Feb 2012Idiopathic pulmonary fibrosis (IPF) is the most common manifestation of telomere-mediated disorders. Germline mutations in the essential telomerase genes, hTERT and hTR,... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is the most common manifestation of telomere-mediated disorders. Germline mutations in the essential telomerase genes, hTERT and hTR, are the causal genetic defect in up to one-sixth of pulmonary fibrosis families. The presence of telomerase mutations in this subset is significant for clinical decisions as affected individuals can develop extra-pulmonary complications related to telomere shortening such as bone marrow failure and cryptogenic liver cirrhosis. There is also evidence that IPF is an ancestral manifestation of autosomal dominant telomere syndromes where, with successive generations, the disease evolves from pulmonary fibrosis into a bone marrow failure-predominant disorder, defining a unique form of genetic anticipation. Here I review the significance of telomere defects for understanding the genetics, disease patterns and pathophysiology of IPF. The importance of this diagnosis for patient care decisions will also be discussed.
Topics: Age Factors; Bone Marrow Diseases; Dyskeratosis Congenita; Emphysema; Genes, Dominant; Genetic Predisposition to Disease; Humans; Pulmonary Fibrosis; Telomerase; Telomere Shortening
PubMed: 22079513
DOI: 10.1016/j.mrfmmm.2011.10.013 -
Hematology/oncology Clinics of North... Aug 2018Clonal hematopoiesis as a hallmark of myelodysplastic syndrome (MDS) is mediated by the selective advantage of clonal hematopoietic stem cells in a context-specific... (Review)
Review
Clonal hematopoiesis as a hallmark of myelodysplastic syndrome (MDS) is mediated by the selective advantage of clonal hematopoietic stem cells in a context-specific manner. Although primary MDS emerges without known predisposing cause and is associated with advanced age, secondary MDS may develop in younger patients with bone marrow failure syndromes or after exposure to chemotherapy, respectively. This article discusses recent advances in the understanding of context-dependent clonal hematopoiesis in MDS with focus on clonal evolution in inherited and acquired bone marrow failure syndromes.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Clonal Evolution; Genetic Predisposition to Disease; Hemoglobinuria, Paroxysmal; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 30047417
DOI: 10.1016/j.hoc.2018.03.005 -
European Journal of Nuclear Medicine... Jan 2011Noninvasive imaging techniques have been used in the past for visualization the functional activity of the bone marrow compartment. Imaging with radiolabelled compounds... (Review)
Review
Noninvasive imaging techniques have been used in the past for visualization the functional activity of the bone marrow compartment. Imaging with radiolabelled compounds may allow different bone marrow disorders to be distinguished. These imaging techniques, almost all of which use radionuclide-labelled tracers, such as (99m)Tc-nanocolloid, (99m)Tc-sulphur colloid, (111)In-chloride, and radiolabelled white blood cells, have been used in nuclear medicine for several decades. With these techniques three separate compartments can be recognized including the reticuloendothelial system, the erythroid compartment and the myeloid compartment. Recent developments in research and the clinical use of PET tracers have made possible the analysis of additional properties such as cellular metabolism and proliferative activity, using (18)F-FDG and (18)F-FLT. These tracers may lead to better quantification and targeting of different cell systems in the bone marrow. In this review the imaging of different bone marrow targets with radionuclides including PET tracers in various bone marrow diseases are discussed.
Topics: Animals; Bone Marrow Diseases; Cell Proliferation; Humans; Radionuclide Imaging
PubMed: 20625724
DOI: 10.1007/s00259-010-1531-0 -
Molecular Genetics & Genomic Medicine May 2018ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and... (Review)
Review
BACKGROUND
ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and craniofacial abnormalities. The aim of this study was to further define the genetic and phenotypic spectrum of the disorder by summarizing the five published cases and an additional case that we identified through whole-exome sequencing performed at the University of Toronto.
METHODS
Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Whole exome sequencing was performed to identify causative mutations.
RESULTS
All six cases had homozygous truncating mutations either at or upstream of the helicase domain of ERCC6L2. All patients displayed bone marrow failure, learning or developmental delay and microcephaly. Our patient was unique in displaying features of cerebellar disease, including ataxia and dysmetria as well as an interval deterioration of the corpus callosum and generalized volume loss on MRI. Another unique feature of our patient was retinal dystrophy with macular involvement. Along with one other patient, our patient displayed craniofacial abnormalities by presenting with low-set prominent ears, a pointed prominent chin, and deep-set eyes. Leukemia is common among patients with inherited bone marrow failure, but thus far, none of the patients have developed this complication.
CONCLUSIONS
ERCC6L2-associated disorder is a multisystem disorder. The phenotype spectrum includes bone marrow failure, cerebral, and craniofacial abnormalities, as well as cerebellar and retinal abnormalities.
Topics: Adolescent; Adult; Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Canada; Child; Child, Preschool; Craniofacial Abnormalities; DNA Helicases; Developmental Disabilities; Exome; Female; Hemoglobinuria, Paroxysmal; Homozygote; Humans; Infant; Intellectual Disability; Male; Microcephaly; Mutation; Nervous System Malformations; Pedigree; Phenotype
PubMed: 29633571
DOI: 10.1002/mgg3.388 -
Blood Jan 2019Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The 2 major modes of programmed cell death, apoptosis and...
Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The 2 major modes of programmed cell death, apoptosis and necroptosis, share molecular machinery but diverge in outcome with important implications for the microenvironment; apoptotic cells are removed in an immune silent process, whereas necroptotic cells leak cellular contents that incite inflammation. Given the importance of cytokine-directed cues for hematopoietic cell survival and differentiation, the impact on hematopoietic homeostasis of biasing cell death fate to necroptosis is substantial and poorly understood. Here, we present a mouse model with increased bone marrow necroptosis. Deletion of the proapoptotic Bcl-2 family members Bax and Bak inhibits bone marrow apoptosis. Further deletion of the BH3-only member Bid (to generate triple-knockout [TKO] mice) leads to unrestrained bone marrow necroptosis driven by increased Rip1 kinase (Ripk1). TKO mice display loss of progenitor cells, leading to increased cytokine production and increased stem cell proliferation and exhaustion and culminating in bone marrow failure. Genetically restoring Ripk1 to wild-type levels restores peripheral red cell counts as well as normal cytokine production. TKO bone marrow is hypercellular with abnormal differentiation, resembling the human disorder myelodysplastic syndrome (MDS), and we demonstrate increased necroptosis in MDS bone marrow. Finally, we show that Bid impacts necroptotic signaling through modulation of caspase-8-mediated Ripk1 degradation. Thus, we demonstrate that dysregulated necroptosis in hematopoiesis promotes bone marrow progenitor cell death that incites inflammation, impairs hematopoietic stem cells, and recapitulates the salient features of the bone marrow failure disorder MDS.
Topics: Animals; BH3 Interacting Domain Death Agonist Protein; Bone Marrow; Bone Marrow Diseases; Cells, Cultured; Cytokines; Hematopoietic Stem Cells; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelodysplastic Syndromes; Necrosis; Receptor-Interacting Protein Serine-Threonine Kinases; bcl-2 Homologous Antagonist-Killer Protein
PubMed: 30413413
DOI: 10.1182/blood-2018-05-847335 -
Hematology. American Society of... Dec 2016Clonal progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) remains a dreaded complication for a subset of patients with bone marrow failure... (Review)
Review
Clonal progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) remains a dreaded complication for a subset of patients with bone marrow failure (BMF). Recognizing risk factors for the development of MDS or AML would inform individualized treatment decisions and identify patients who may benefit from early or upfront hematopoietic stem cell transplantation. Now that next-generation DNA sequencing is available in the clinical laboratory, research has focused on the implications of germ line and somatic mutations for diagnosing and monitoring patients with BMF. Most germ line genetic BMF disorders are characterized by a high propensity to develop MDS or AML. Many affected patients lack the physical stigmata traditionally associated with the inherited marrow failure syndromes. Although any single inherited marrow failure disorder is rare, multiplexed genetic sequencing that allows simultaneous evaluation of marrow failure genes en masse demonstrated that, as a group, these inherited disorders compose a significant subset (5% to 10%) of patients with BMF. Early diagnosis of a germ line genetic marrow failure disorder allows individualized monitoring and tailored therapy. Recent studies of somatic variants in marrow failure revealed a high frequency of clonal hematopoiesis with the acquisition of mutations in genes associated with MDS or AML. Investigation of somatic mutations in marrow failure revealed important insights into the mechanisms promoting clonal disease but also raised additional questions. This review will focus on the evaluation and implications of germ line and somatic mutations for the development of clonal disorders in patients with BMF. Challenges and limitations of clinical genetic testing will be explored.
Topics: Anemia, Aplastic; Genetic Diseases, Inborn; Germ-Line Mutation; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 27913465
DOI: 10.1182/asheducation-2016.1.74 -
International Journal of Molecular... Apr 2023Bone marrow edema (BME), also termed bone marrow lesions, is a syndrome characterized by bone pain and the appearance of high signal intensity on T2 fat-suppressed and...
Bone marrow edema (BME), also termed bone marrow lesions, is a syndrome characterized by bone pain and the appearance of high signal intensity on T2 fat-suppressed and short tau inversion recovery (STIR) MRI sequences. BME can be related to trauma or a variety of non-traumatic diseases, and current treatment modalities include non-steroidal anti-inflammatory drugs (NSAIDS), bisphosphonates, denosumab, extracorporeal shockwave therapy (ESWT), the vasoactive prostacyclin analogue iloprost, and surgical decompression. Spontaneous BME is a subset that has been observed with no apparent causative conditions. It is most likely caused by venous outflow obstruction and intraosseous hypertension. These are mechanistically related to impaired perfusion and ischemia in several models of BME and are related to bone remodeling. The association of perfusion abnormalities and bone pain provides the pathophysiological rationale for surgical decompression. We present a case of spontaneous BME and a second case of spontaneous migratory BME treated with surgical decompression and demonstrate resolution of pain and the high signal intensity on MRI. This report provides an integration of the clinical syndrome, MR imaging characteristics, circulatory pathophysiology, and treatment. It draws upon several studies to suggest that both the bone pain and the MRI characteristics are related to venous stasis, and when circulatory pathologies are relieved by decompression or fenestration, both the bone pain and the MRI signal abnormalities resolve.
Topics: Humans; Bone Marrow; Bone Marrow Diseases; Bone Diseases; Edema; Decompression, Surgical; Magnetic Resonance Imaging; Musculoskeletal Pain; Perfusion
PubMed: 37047734
DOI: 10.3390/ijms24076761