Missing Cells: Pathophysiology, Diagnosis, and Management of (Pan)Cytopenia in Childhood

Erlacher, Miriam; Strahm, Brigitte

doi:10.3389/fped.2015.00064

Cited by 31 publications

(38 citation statements)

References 153 publications

(152 reference statements)

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“…This has been implicated in the pathogenesis of Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and others (see below and Table 2). Expectedly, these syndromes have high pressure to inactivate DNA damage checkpoint signaling, as reflected by a high incidence of myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML) [152]. The impact of apoptosis signaling in p53-mediated bone marrow failure has only been investigated in part, as depicted in Table 2.…”

Section: The Role Of P53 Beyond Dna Damage Responsementioning

confidence: 99%

“…Depending on the lineage affected, the leading symptoms are anemia (erythroid), thrombocytopenia (megakaryocytic), or susceptibility to infection (myeloid and/or lymphatic). Pancytopenia is the result of a defect in all lineages or within the multipotent HSPC pool [152]. Most diseases are not exclusively characterized by increased susceptibility to apoptosis but additionally by a block in differentiation or disturbed cellular structures or functions.…”

Section: Hematological Diseases With Excessive Apoptosismentioning

confidence: 99%

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Bcl‐2 proteins in development, health, and disease of the hematopoietic system

et al. 2016

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Members of the Bcl‐2 protein family regulate cell fate decisions following a variety of developmental cues or stress signals, with the outcomes of cell death or survival, thus shaping multiple mammalian tissues. This review describes in detail how anti‐ and proapoptotic Bcl‐2 proteins contribute to the development and functioning of the fetal and adult hematopoietic systems and how they influence the generation and maintenance of different hematopoietic lineages. An overview on how stress signals such as genotoxic stress or inflammation can compromise blood cell production, partially by engaging the intrinsic apoptosis pathway, is presented. Finally, the review describes how Bcl‐2 protein deregulation—either leading to increased apoptosis resistance or excessive cell death—contributes to many hematological disorders, with specific focus on rare disorders of hematopoiesis and how this knowledge may be used therapeutically.

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Section: The Role Of P53 Beyond Dna Damage Responsementioning

confidence: 99%

Section: Hematological Diseases With Excessive Apoptosismentioning

confidence: 99%

Bcl‐2 proteins in development, health, and disease of the hematopoietic system

et al. 2016

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“…The mechanism of this adaptation appears to differ in deep hibernators like ground squirrels, which show some loss of bone cells, while shallower hibernators like bears retain their cellular integrity (101). Understanding the molecular adaptations (3) in bone marrow that allow hibernating mammals to avoid damage could have direct clinical applications in human disorders that affect blood cell numbers and bone loss due to disuse (29,38,39,82,91). In this study the bone marrow transcriptome from July nonhibernating, winter torpid, and winter IBA ground squirrels was analyzed for potential impacts on bone metabolism and blood cell activity.…”

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confidence: 99%

Effects of hibernation on bone marrow transcriptome in thirteen-lined ground squirrels

Cooper

Sell

Fahrenkrog

et al. 2016

Physiological Genomics

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M. Effects of hibernation on bone marrow transcriptome in thirteen-lined ground squirrels. Physiol Genomics 48: 513-525, 2016. First published May 20, 2016 doi:10.1152/physiolgenomics.00120.2015.-Mammalian hibernators adapt to prolonged periods of immobility, hypometabolism, hypothermia, and oxidative stress, each capable of reducing bone marrow activity. In this study bone marrow transcriptomes were compared among thirteen-lined ground squirrels collected in July, winter torpor, and winter interbout arousal (IBA). The results were consistent with a suppression of acquired immune responses, and a shift to innate immune responses during hibernation through higher complement expression. Consistent with the increase in adipocytes found in bone marrow of hibernators, expression of genes associated with white adipose tissue are higher during hibernation. Genes that should strengthen the bone by increasing extracellular matrix were higher during hibernation, especially the collagen genes. Finally, expression of heat shock proteins were lower, and cold-response genes were higher, during hibernation. No differential expression of hematopoietic genes involved in erythrocyte or megakaryocyte production was observed. This global view of the changes in the bone marrow transcriptome over both short term (torpor vs. IBA) and long term (torpor vs. July) hypothermia can explain several observations made about circulating blood cells and the structure and strength of the bone during hibernation. erythrocyte; leukocyte; megakaryocyte; osteoblast; adipose BONE MARROW IS A COMPLEX ORGAN consisting of many different cell types and stem cell pools. These cells express both unique and common sets of genes and likely influence each other's activities. Hematopoietic stem cells can differentiate into lymphoid progenitor cells that produce natural killer cells and lymphocytes, or into myeloid progenitor cells that give rise to erythrocytes, the remaining leukocytes, and megakaryocytes. Megakaryocytes in turn shed anucleated platelets involved in blood clotting and inflammation. Bone marrow resident mesenchymal stem cells can differentiate to produce resident bone cells including osteoblasts, adipocytes, and chondrocytes (64). Osteoblasts can terminally differentiate into osteocytes and are involved in maintaining bone strength and extracellular matrix production. Bone marrow adipose composition is affected by age, diet, and disease states. Bone marrow may also contain skeletal muscle and hepatocyte stem cell pools. Because of the rapid rate of mitosis by multiple resident stem cell pools, bone marrow is sensitive to damage by radiation and chemotherapy, leaving patients immunocompromised and anemic (25). Bone mineral density and collagen are decreased by prolonged disuse such as bed rest or immobilization (45,86). Recent studies have also demonstrated an increase in neutrophils, natural killer cells, and lymphocytes and a decrease in monocytes in patients subjected to 60 days of bed rest (38). Finally, bone marrow adipocytes increase in ...

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“…(14)(15)(16) Chest radiograph performed before insertion of a central vein catheter, showed increased bone intensity and aftereffects of fractures in both humeri. He was born from an Italian mother and a Moroccan father, through Caesarean section at week 39 of gestation because of bradycardia.…”

Section: Patients and Samplesmentioning

confidence: 99%

Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

Palagano

Susani

Menale

et al. 2016

Journal of Bone and Mineral Research

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Autosomal recessive osteopetroses (AROs) are rare, genetically heterogeneous skeletal diseases with increased bone density that are often lethal if left untreated. A precise molecular classification is relevant for the patient's management, because in some subgroups hematopoietic stem cell transplantation (HSCT), which is the only curative therapy, is contraindicated. In two unrelated ARO patients, the molecular analysis revealed the presence of a synonymous variant in known ARO genes, namely in the TCIRG1 gene in one patient and in the CLCN7 in the other patient, predicted to impact on the splicing process. In the latter case, sequencing of the transcript confirmed the splicing defect, whereas in the former, for whom an RNA sample was not available, the defect was reconstructed in vitro by the minigene technology. These results strongly suggest that these synonymous changes were responsible for the disease in our patients. Our findings are novel with respect to ARO and add to the few reports in literature dealing with different diseases, underlining the importance of cDNA analysis for the correct assessment of exonic changes, even when exome sequencing is performed. In particular, we highlight the possibility that at least in some cases ARO is due to synonymous changes, erroneously considered clinically silent, in the genes already described in literature, and suggest carefully reevaluating the sequencing results of these genes when mutations are not found at a first analysis. In addition, with respect to the CLCN7 gene, we suggest that synonymous variants might also contribute to the large spectrum of severity typical of CLCN7-dependent osteopetrosis through more subtle, but not negligible, effects on protein availability and functionality. © 2016 American Society for Bone and Mineral Research.

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Missing Cells: Pathophysiology, Diagnosis, and Management of (Pan)Cytopenia in Childhood

Cited by 31 publications

References 153 publications

Bcl‐2 proteins in development, health, and disease of the hematopoietic system

Bcl‐2 proteins in development, health, and disease of the hematopoietic system

Effects of hibernation on bone marrow transcriptome in thirteen-lined ground squirrels

Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

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