Reed-Sternberg Cells Have Shortened Telomere Length.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4594-4594
Author(s):  
Jonathan M. Ben-Ezra ◽  
Colleen Jackson-Cook
Keyword(s):  
Telomere Length ◽  
Hodgkin Lymphoma ◽  
Chromosomal Instability ◽  
Soft Tissue Tumors ◽  
Hybridization Signal ◽  
Probe Signal ◽  
Neoplastic Cells ◽  
Normal Cells ◽  
Telomere Probe ◽  
Chromosomal Length

Abstract As cells age, the ends of their chromosomes, the telomeres, become shortened. The chromosomal length eventually shortens to a critical point, which is thought to lead to chromosomal instability and/or cell death. Neoplastic cells have increased amounts of telomerase, an enzyme that prevents this shortening; this may be one mechanism by which tumor cells grow. Due to the scarcity of neoplastic Reed-Sternberg cells in tissues of Hodgkin Lymphoma, studies of telomere length and telomerase expression have been difficult and few. These few studies have tended to show an increase in telomerase expression in tissues from Hodgkin Lymphoma. In order to determine telomere length in Reed-Sternberg cells, we performed an immunofluorescence/FISH assay using a PNA pantelomeric probe and a CD30 antibody with which to identify the Reed-Sternberg cells (Am J Pathol 160:1259–68, 2002). Six cases were studied, with patient ages ranging from 18– 51 years. Telomere length was assessed on a semiquantitative scale. Of the six cases, five had evaluable hybridization signal. In these five cases, 53 CD30-positive cells (between 3–20 per case) were studied. In forty cells, the hybridization signal (telomere length) was less than that of surrounding cells, and in 13 it was the same; in no case was telomere length greater in the Reed-Sternberg cell than in surrounding lymphocytes (p< 0.001, Wilcoxon signed ranks test). There was no correlation between the age of the patient or the age of the sample and telomere probe signal intensity/quantity. Similar to epithelial and soft tissue tumors, it appears that the neoplastic cells in Hodgkin Lymphoma have shortened telomere length as compared to the surrounding normal cells.

scholarly journals Hodgkin Lymphoma: A Special Microenvironment

2021 ◽  
Vol 10 (20) ◽  
pp. 4665
Author(s):  
Giuseppina Opinto ◽  
Claudio Agostinelli ◽  
Sabino Ciavarella ◽  
Attilio Guarini ◽  
Eugenio Maiorano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Expression Profiling ◽  
Neoplastic Cells ◽  
Normal Cells ◽  
Growth And Survival ◽  
Inflammatory Microenvironment ◽  
Cellular Components

Classical Hodgkn’s lymphoma (cHL) is one of the most particular lymphomas for the few tumor cells surrounded by an inflammatory microenvironment. Reed-Sternberg (RS) and Hodgkin (H) cells reprogram and evade antitumor mechanisms of the normal cells present in the microenvironment. The cells of microenvironment are essential for growth and survival of the RS/H cells and are recruited through the effect of cytokines/chemokines. We summarize recent advances in gene expression profiling (GEP) analysis applied to study microenvironment component in cHL. We also describe the main therapies that target not only the neoplastic cells but also the cellular components of the background.

Localization of Gallium-67 in Peritoneal Cells by Electron Microscopic Autoradiography

1973 ◽  
Vol 31 ◽  
pp. 404-405
Author(s):  
D. C. Swartzendruber ◽  
Norma L. Idoyaga-Vargas
Keyword(s):  
Clinical Trials ◽  
Soft Tissue ◽  
Tumor Tissue ◽  
Soft Tissue Tumors ◽  
Clinical Usefulness ◽  
Electron Microscopic ◽  
Normal Cells ◽  
Electron Microscopic Autoradiography ◽  
Peritoneal Cells ◽  
Gallium 67

The radionuclide gallium-67 (67Ga) localizes preferentially but not specifically in many human and experimental soft-tissue tumors. Because of this localization, 67Ga is used in clinical trials to detect humar. cancers by external scintiscanning methods. However, the fact that 67Ga does not localize specifically in tumors requires for its eventual clinical usefulness a fuller understanding of the mechanisms that control its deposition in both malignant and normal cells. We have previously reported that 67Ga localizes in lysosomal-like bodies, notably, although not exclusively, in macrophages of the spocytaneous AKR thymoma. Further studies on the uptake of 67Ga by macrophages are needed to determine whether there are factors related to malignancy that might alter the localization of 67Ga in these cells and thus provide clues to discovering the mechanism of 67Ga localization in tumor tissue.

scholarly journals The wages of CIN

2008 ◽  
Vol 180 (4) ◽  
pp. 661-663 ◽  
Author(s):  
Karen W. Yuen ◽  
Arshad Desai
Keyword(s):  
Cancer Cells ◽  
Solid Tumors ◽  
Chromosomal Instability ◽  
Chromosome Instability ◽  
Spindle Checkpoint ◽  
Human Cells ◽  
Normal Cells ◽  
Chromosome Missegregation ◽  
Cell Biol ◽  
The Relationship

Aneuploidy and chromosome instability (CIN) are hallmarks of the majority of solid tumors, but the relationship between them is not well understood. In this issue, Thompson and Compton (Thompson, S.L., and D.A. Compton. 2008. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell. Biol. 180:665–672) investigate the mechanism of CIN in cancer cells and find that CIN arises primarily from defective kinetochore–spindle attachments that evade detection by the spindle checkpoint and persist into anaphase. They also explore the consequences of artificially elevating chromosome missegregation in otherwise karyotypically normal cells. Their finding that induced aneuploidy is rapidly selected against suggests that the persistence of aneuploid cells in tumors requires not only chromosome missegregation but also additional, as yet poorly defined events.

scholarly journals A Prospective Study of Telomere Length Measured by Monochrome Multiplex Quantitative PCR and Risk of Non-Hodgkin Lymphoma

2009 ◽  
Vol 15 (23) ◽  
pp. 7429-7433 ◽  
Author(s):  
Q. Lan ◽  
R. Cawthon ◽  
M. Shen ◽  
S. J. Weinstein ◽  
J. Virtamo ◽  
...  
Keyword(s):  
Prospective Study ◽  
Telomere Length ◽  
Hodgkin Lymphoma ◽  
Quantitative Pcr ◽  
Non Hodgkin Lymphoma ◽  
A Prospective Study

Molecular analyses of adaptive survival responses (ASRs): role of ASRs in radiotherapy

1998 ◽  
Vol 17 (8) ◽  
pp. 448-453 ◽  
Author(s):  
David A Boothman ◽  
Eric Odegaard ◽  
Chin-Rang Yang ◽  
Kelly Hosley ◽  
Marc S Mendonca
Keyword(s):  
Cell Cycle ◽  
Stress Responses ◽  
Strand Break ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints ◽  
Specific Gene ◽  
High Dose ◽  
Neoplastic Cells ◽  
Normal Cells ◽  
Cycle Checkpoint

Adaptive survival responses (ASRs), whereby cells demonstrate a survival advantage when exposed to very low doses of ionizing radiation (IR) 4-24 h prior to a high dose challenge, were first reported over 15 years ago. These responses were linked to hormesis, which implied that exposure to low levels of IR may be beneficial to the cell. We postulate that increased survival does not necessarily mean that the treatment is beneficial.Studies at the molecular level indicate that ASRs are the result of misregulated cell cycle checkpoint responses, occurring in the G1 phase of the cell cycle after IR. Specific gene products (i.e., PCNA, cyclin D1, cyclin A, XIP8, xip5 and xip13) appear to control these cell cycle checkpoint responses. Certain neoplastic cells show potent ASRs because they bypass checkpoints which would otherwise lead to apoptosis or other forms of cell death (possibly necrosis), and/or these cancer cells lack genetic factors, such as specific caspases (cysteine aspartate-specific proteases), that control apoptosis. Alterations in these cell cycle checkpoints or apoptotic responses may also occur during IR-induced stress responses in normal cells, at critical times (10-18 days posttreatment) following IR. One IR-induced protein, XIP8, may be a critical controlling factor at this point where delayed-onset apoptosis occurs. Additionally, we have shown that the presence or absence (i.e., SCID cells) of nonhomologous DNA double strand break repair did not seem to influence ASRs, suggesting that ASRs may be caused by signal transduction stress responses.ASRs may be beneficial to survival, however, the consequence(s) of that survival may be dire. For example, many neoplastic cells exhibited far greater ASRs than normal cells. Additionally, ASRs were induced by as little as 1 cGy and and were enhanced by repeated exposures of low level radiation. The implications for radiotherapy are that when a patient arrives for port film imaging during the course of therapy, the dose-rate, overall level of exposure, and time between port film exposure and high dose IR treatment become potentially important factors for improved efficacy of treatment of certain cancers. Further research is warranted to determine what molecular factors are most important for ASRs, and current work is focusing on XIP8.

Rapid Telomere Loss in Hematopoietic Cells Associated with Development of t-MDS after Autologous Transplantation for Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2644-2644
Author(s):  
Sujata Chakraborty ◽  
C.-L. Sun ◽  
L. Francisco ◽  
A. Komiya ◽  
H. Damasco ◽  
...  
Keyword(s):  
Telomere Length ◽  
Hodgkin Lymphoma ◽  
Hematopoietic Cells ◽  
Myeloid Cells ◽  
Hematopoietic Cell ◽  
Initial Increase ◽  
Hematopoietic Stem ◽  
Telomere Regulation ◽  
Telomere Dynamics ◽  
Over Time

Abstract Therapy-related MDS (t-MDS) is a lethal complication of autologous hematopoietic cell transplantation (HCT) for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Although t-MDS is known to result from damage to hematopoietic stem cells (HSC) from genotoxic cancer treatment, the sequential cellular and molecular changes leading to its development are not known. To better understand t-MDS pathogenesis we are conducting a prospective study of a cohort of patients undergoing autologous HCT for HL and NHL. Patients are followed longitudinally from pre-HCT to 5 yrs post-HCT, with serial collection of marrow and blood samples. We investigated whether development of t-MDS after HCT was associated with altered telomere dynamics in hematopoietic cells. Telomeres are non-coding sequences at ends of chromosomes. Telomere shortening may be associated with genetic instability and myeloid leukemogenesis, and could predispose to t-MDS after HCT. Telomere length was measured in peripheral blood (PB) samples from 8 patients from the cohort who developed t-MDS after HCT and 24 matched controls who did not develop t-MDS (3 controls per case: matched for primary diagnosis, age at HCT, race and length of follow-up). Samples were analyzed pre-HCT and at d100, 6 months, 1 yr and then annually post-HCT till development of t-MDS. PB cells were mixed with equal numbers of 1301 cells, as internal controls, and hybridized with a telomere PNA-FITC probe. Relative telomere length (RTL) values (ratio of telomere signal of PB sample and control 1301 cells) were determined by flow cytometry (FlowFISH). RTL values of lymphoid and myeloid cells, identified by scatter properties, were separately analyzed. The median PBSC CD34+ count (106/kg) for cases was 4.9 (2.6–17.4) and controls was 5.2 (2.1–33.5). Differences in RTL were seen at several time points in t-MDS cases and controls for total cell, lymphoid and myeloid cells, but were most marked in the myeloid cells. Patients developing t-MDS showed reduced RTL pre-HCT (myeloid RTL: cases=18.2±4.8, controls=27.2±2.8); an increase in RTL at d 100 (myeloid RTL for cases=31.4±4.6, controls=19.6±2.5, p=0.04); and progressive reduction in RTL subsequently (myeloid RTL at 3 years: cases= 9.7±4.1, controls=22.0±2.2). An increase in RTL from pre-BMT to d 100 was seen in t-MDS patients (+16.0) but not in controls (−8.2) (p=0.004). A fixed effect growth curve model fitted to the data from d100 to 3 years to examine the rate of change in RTLs over time revealed a sharp decline in RTL for cases (β per 100 days = −1.93 for myeloid cells), but no change in RTL over time for controls (β = 0.07) (p = 0.02). In summary, we observed severely altered telomere dynamics in hematopoietic cells from patients who develop t-MDS post-HCT, with an initial increase in telomere length followed by a very sharp rate of telomere attrition till development of t-MDS. The initial increase in telomere length may reflect a need for increased recruitment of fresh HSC, with longer telomeres, to achieve hematopoietic recovery post-HCT. Subsequent rapid attrition of telomere length may reflect increased hematopoietic cell proliferation associated with ineffective hematopoiesis characteristic of MDS or represent altered telomere regulation in damaged HSC. Altered telomere regulation and reduced telomere length may contribute to leukemic transformation of HSC in t-MDS.

Thioredoxin-1, chemokine (C-X-C motif) ligand-9 and interferon-γ expression in the neoplastic cells and macrophages of Hodgkin lymphoma: clinicopathologic correlations and potential prognostic implications

2017 ◽  
Vol 58 (9) ◽  
pp. 2227-2239 ◽  
Author(s):  
Theodoros P. Vassilakopoulos ◽  
Georgia Levidou ◽  
Vassilis Milionis ◽  
Sylvia Hartmann ◽  
Eleftheria Lakiotaki ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Interferon Γ ◽  
Neoplastic Cells ◽  
Thioredoxin 1 ◽  
Prognostic Implications

scholarly journals Formation of the Immunosuppressive Microenvironment of Classic Hodgkin Lymphoma and Therapeutic Approaches to Counter It

2019 ◽  
Vol 20 (10) ◽  
pp. 2416 ◽  
Author(s):  
Donatella Aldinucci ◽  
Cinzia Borghese ◽  
Naike Casagrande
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
T Cell Exhaustion ◽  
Normal Cells ◽  
Cell Exhaustion ◽  
Classic Hodgkin Lymphoma

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed–Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and “educate” (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

scholarly journals Novel Germline POT1 Variant Predisposes to Childhood Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3449-3449
Author(s):  
Pia Michler ◽  
Franziska Auer ◽  
Rabea Wagener ◽  
Triantafyllia Brozou ◽  
Ulrike Anne Friedrich ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Telomere Length ◽  
Chromosomal Instability ◽  
Myeloid Leukemia ◽  
T Test ◽  
Qrt Pcr ◽  
Student’S T ◽  
Acute Myeloid ◽  
Student’S T Test

Abstract Introduction: Current studies indicate a contribution of germline predisposition in the development of approximately 8.5% of childhood cancers (Zhang J. et al., N Engl J Med, 2015), although their apparent rate is estimated to be much higher. Understanding tumor evolution based on a predisposed cell can open unknown doors for prevention and therapy of childhood cancer e.g., leukemia. Here we present a novel rare (MAF<0.1%) germline POT1 variant (Q199*) predisposing to acute myeloid leukemia (AML). POT1 as part of the telomeric shelterin complex is known to play an important role in DNA damage protection, telomere length maintenance and chromosomal stability (Calvete O. et al., Nat. Commun., 2015). POT1 variants are associated with a broad range of cancer, including myeloid and lymphoid neoplasms in adults (Lim T.L. et al., Leukemia, 2021), but not yet described for myeloid malignancies in childhood. Methods: Whole exome sequencing (WES) was implemented to identify germline variants. To assess the effect of POT1 p.Q199*, patient's fibroblast and stably transfected HEK293T cells were used as cell models. The variant's functional impact was experimentally tested performing yH2AX and 53BP1 immunofluorescence assays for DNA damage detection, qRT-PCR for telomere length measurement and telomere FISH to assess chromosomal instability. Results: Utilizing WES to detect variants within shelterin complex genes we analyzed genomic data of an unselected German parent-child cohort of children with cancer (n=60, TRIO-DD), as well as a recently published parent-child pediatric cancer cohort (n=158, TRIO-D) (Wagener R. et al., Eur. J. Hum. Genet, 2021). Here, we identified a novel germline POT1 variant in a boy affected with Myelodysplastic syndrome (MDS) and secondary AML (7q-). This novel germline variant constitutes a stop-gain mutation causing a substitution of the amino acid Glutamine by a stop codon (p.Q199*). QRT-PCR analysis within the patient's fibroblasts showed a significant (student's t-test p=0.0037) reduction of POT1 mRNA expression to ≈0.5 compared to POT1 wildtype. Western Blot analysis revealed reduced POT1 levels, confirming the loss of one POT1 allele mediated by p.Q199*. Thereupon, POT1 p.Q199* cloning and stable transfection into Hek293T cells was performed to test the variant's cooperative functionality in a controlled environment. Subsequently, POT1 p.Q199* lead to a drastically significant (student's t-test p=<0.001) increase of DNA double strand breaks in transfected Hek293T cells determined by yH2AX and 53BP1 immunofluorescence assays, which is in line with a deregulated DNA damage response and inappropriate repair by non-homologous end joining. In addition, we detected dysregulation of telomere length maintenance. Here, relative telomere length measurement by means of qRT-PCR indicated significant (student's t-test p=0.019) telomere elongation in POT1 p.Q199* fibroblast cells. Furthermore telomere FISH on metaphase chromosomes was performed to analyse chromosomal stability. In POT1 p.Q199* Hek293T cells we identified a significant (student's t-test p=0.002) increase in telomere fragility compared to POT1 WT cells. Conclusion: Taken together, we present the functional effects of POT1 p.Q199* leading to a significant increase of DNA damage, telomere length and chromosomal instability. Our results on functional dysregulation strengthen a potential genetic predisposition to childhood AML mediated by germline POT1 variants. Disclosures No relevant conflicts of interest to declare.

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