Indirect evidence of TTV replication in bone marrow cells, but not in hepatocytes, of a subacute hepatitis/aplastic anemia patient

Abstract Three patients with different obscure hematologic disorders are presented. All 3 patients had abnormalities of chromosome number confined to marrow cells. Case 1 is a 23-year-old man with aplastic anemia; most of his bone marrow cells contained 45 chromosomes, with one missing from group C. Case 2 is a 62-year-old man who died of idiopathic sideroachrestic anemia; most of his bone marrow cells contained 47 chromosomes with an extra C group chromosome which appeared to be an autosome. Case 3 is a 59-year-old woman with idiopathic thrombocythemia; while the majority of her bone marrow cells contained 46 chromosomes, a stable minority cell line had 48 chromosomes. Although many of the reported patients with myelodysplastic-myeloproliferative disorders have normal chromosomes, 5 cases with some chromosomal aberration, previously reported by others, are summarized. None of these patients had clinical evidence of leukemia. In 4 of the patients, the chromosomal anomaly involved a chromosome in group C, which is the group in which aneuploidy occurred in all 3 of our patients. It is postulated that a stable, aneuploid stem line does not of itself produce neoplasia, but rather that this alteration of the genome may provide a more favorable milieu for the action of some transforming agent. Because of the frequent occurrence of C group abnormalities in these cases of marrow disorders, it is further postulated that genes on one or more C chromosomes might be responsible for homeostatic control of hemopoiesis, and that a change in genetic balance involving a C group chromosome(s) coupled with a transforming agent might result in leukemia in a greater proportion of individuals than aneuploidy of some other chromosomal group.

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Treatment options and nursing care for the pediatric aplastic anemia patient requriring bone marrow or stem cell transplantation

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2004.12.291 ◽

2005 ◽

Vol 11 (2) ◽

pp. 98

Author(s):

J.H. Baker ◽

M.A. Frey ◽

J. Kurtzberg

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Aplastic Anemia ◽

Cell Transplantation ◽

Nursing Care ◽

Treatment Options ◽

Aplastic Anemia Patient ◽

Anemia Patient

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Increased Expression of Fas Antigen and Apoptosis in Aplastic Anemia Bone Marrow Cells

Immune Network ◽

10.4110/in.2002.2.1.53 ◽

2002 ◽

Vol 2 (1) ◽

pp. 53

Author(s):

Jong Ho Won ◽

Nam Su Lee ◽

Sook Ja Kim ◽

Hee Jeong Cheong ◽

Kyu Taeg Lee ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Bone Marrow Cells ◽

Fas Antigen ◽

Marrow Cells

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Expression of the proliferating cell nuclear antigen in bone marrow cells from patients with myelodysplastic syndromes and aplastic anemia

Human Pathology ◽

10.1016/0046-8177(93)90082-r ◽

1993 ◽

Vol 24 (4) ◽

pp. 359-363 ◽

Cited By ~ 20

Author(s):

Masanobu Kitagawa ◽

Ryuichi Kamiyama ◽

Tsutomu Kasuga

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Myelodysplastic Syndromes ◽

Proliferating Cell Nuclear Antigen ◽

Bone Marrow Cells ◽

Nuclear Antigen ◽

Proliferating Cell ◽

Marrow Cells

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Stem cell defect in aplastic anemia: reduced long term culture-initiating cells (LTC-IC) in CD34+ cells isolated from aplastic anemia patient bone marrow

The Hematology Journal ◽

10.1038/sj.thj.6200187 ◽

2002 ◽

Vol 3 (5) ◽

pp. 230-236 ◽

Cited By ~ 26

Author(s):

Sian Rizzo ◽

John Scopes ◽

Modupe O Elebute ◽

Helen A Papadaki ◽

Edward C Gordon-Smith ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Aplastic Anemia ◽

Long Term Culture ◽

Aplastic Anemia Patient ◽

Cd34 Cells ◽

Anemia Patient ◽

Cell Defect

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Telomere Shortening Promotes Chromosomal Instability and Predicts Malignant Clonal Evolution in Aplastic Anemia.

Blood ◽

10.1182/blood.v114.22.3208.3208 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3208-3208

Author(s):

Rodrigo T. Calado ◽

James N Cooper ◽

Phillip Scheinberg ◽

Colin Wu ◽

Marco A Zago ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Telomere Length ◽

Malignant Transformation ◽

Chromosomal Instability ◽

Bone Marrow Cells ◽

Clonal Evolution ◽

Monosomy 7 ◽

Marrow Cells

Abstract Abstract 3208 Poster Board III-145 In murine models, telomere erosion promotes chromosomal instability via breakage-fusion-bridge cycles, contributing to the early stages of tumorigenesis. However, direct evidence that short telomeres predispose to cancer development in humans is lacking. In acquired aplastic anemia, evolution to malignant clonal disorders is a major complication after immunosuppressive therapy, affecting up to 15 percent of patients at 10 years. We investigated whether telomere length measured at diagnosis predicted clonal evolution in these patients. Telomere length was measured from DNA extracted from peripheral blood leukocytes collected at disease presentation in 183 consecutive patients enrolled in successive clinical trials for immunosuppressive regimen as first line therapy for severe aplastic anemia at the Clinical Research Center, National Institutes of Health (ClinicalTrials.gov identifier numbers, NCT00001964, NCT00260689, and NCT00061360) and 164 healthy volunteers. Leukocyte telomere length of aplastic anemia patients at diagnosis was in the normal range and was not shorter than in healthy controls (ANOVA-F test). Telomere length was corrected for age and patients were separated into two groups: patients with short telomeres (in the lowest quartile) and long telomeres (other quartiles). Telomere length was a critical and independent predictive biomarker for evolution to myelodysplastic syndrome, especially monosomy 7, and acute myeloid leukemia (AML) in patients with acquired aplastic anemia (Multivariate Cox Proportional Hazard Model, P=0.006). Patients with short telomeres had six-fold higher probability to develop clonal malignant disease than did patients with longer telomeres. Bone marrow cells of aplastic patients were cultured in vitro for short term in the presence of cytokines and high-dose granulocyte-colony stimulating factor (G-CSF) and cells of patients with short telomeres (n=5) showed increased telomere-free chromosomal ends in comparison to cells of patients with long telomeres (n=6), by fluorescence in situ hybridization (FISH; P<0.0001). Spectral karyotyping (SKY) revealed that cultured bone marrow cells of patients with short telomeres exhibited aneuploidy and translocations, including Robertsonian translocations, which were not found in cells of patients with long telomeres. Bone marrow cells at diagnosis were further evaluated for the presence of monosomy 7 cells using interphase FISH in 73 patients. Telomere length inversely correlated with the frequency of monosomy 7 cells: the shortest the telomeres, the highest the percentage of aneuploid cells at diagnosis (Pearson r=-0.5110; P=0.0009). We further employed bone marrow cells of clinically healthy individuals carrying loss-of-function telomerase mutations and with extremely short telomeres (n=5) as a model for telomere dysfunction in hematopoietic cells in the absence of human disease. In vitro culture of these cells yielded aberrant karyotypes by SKY, including translocations and aneuploidy, and end-to-end chromosomal fusions by FISH. These results indicate that telomere length at diagnosis predicts evolution to myelodysplasia and leukemia in patients with acquired aplastic anemia treated with immunosuppression. Our findings support the hypothesis that short and dysfunctional telomeres restrain stem cell proliferation and predispose for malignant transformation by selecting stem cells that are prone to chromosomal instability. This is the first prospective study to demonstrate that short telomeres in human hematopoietic cells promote chromosomal instability in vitro and predispose to malignant transformation in humans. Disclosures Cooper: NIH-Pfizer: Research Funding.

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Single-Cell RNA-Seq of Bone Marrow Cells in Aplastic Anemia

Frontiers in Genetics ◽

10.3389/fgene.2021.745483 ◽

2022 ◽

Vol 12 ◽

Author(s):

Hu Tonglin ◽

Zhao Yanna ◽

Yu Xiaoling ◽

Gao Ruilan ◽

Yin Liming

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

Aplastic Anemia ◽

Single Cell ◽

Differentially Expressed Genes ◽

Bone Marrow Cells ◽

Bone Marrow Failure ◽

Differentially Expressed ◽

Marrow Cells

Aplastic anemia (AA) is an autoimmune disease characterized by peripheral blood pancytopenia and bone marrow failure. Recently, a research study verified bone marrow failure of AA patients resulting from hematopoietic stem and progenitor cell (HSPC) attack by active T cells. Nonetheless, whether B cells, as one of the important immune cells, destruct the hematopoiesis is still unclear. Here, a large-scale single-cell transcriptomic sequencing of 20,000 bone marrow cells from AA patients and healthy donors was performed. A total of 17 clusters and differentially expressed genes were identified in each cluster relative to other clusters, which were considered potential marker genes in each cluster. The top differentially expressed genes in HSPCs (S100A8, RETN, and TNFAIP3), monocytes (CXCL8, JUN, and IL1B), and neutrophils and granulocytes (CXCL8, NFKBIA, and MT-CYB) were related to immune and inflammatory injury. Then, the B-cell receptor (BCR) diversities and pairing frequencies of V and J genes were analyzed. The highest pairing frequencies in AA patients were IGHV3-20-IGKJ2, IGHV3-20-IGKJ4, and IGHV3-20-IGHLJ2. Meanwhile, there were 3 V genes, including IGHV3-7, IGHV3-33, and IGLV2-11, with elevated expression in B cells from AA patients. Cell type–specific ligand–receptor was further identified in B-cell interaction with hematopoietic cells in the bone marrow. The changed ligand–receptor pairs involved antigen presentation, inflammation, apoptosis, and proliferation of B cells. These data showed the transcriptomic landscape of hematopoiesis in AA at single-cell resolution, providing new insights into hematopoiesis failure related with aberrance of B cells, and provide available targets of treatment for AA.

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