Fig 1 - uploaded by Christine M Morris
Content may be subject to copyright.
Five pairs of chromosomes showing telomeric association (TA) from leukemic bone marrow cells of Patient H
Source publication
About 20% of leukemic bone marrow cells from each of two patients with B-cell lymphoid leukemias showed apparent translocations which appeared to be the result of telomeric association. In one patient, whole chromosomes were associated telomere to telomere in pairs; in the other patient, telomeres of whole chromosomes were associated with breakpoin...
Context in source publication
Context 1
... H. The most consistent cytogenetic abnormality in the bone marrow of this patient when leukemia was diagnosed was a 17p+ chromosome (Table 1). The breakpoint of 17p and the origin of the additional short arm material could not be determined. Terminal associations (TA) between two complete chromosomes were observed in a total of nine cells from the bone marrow and leukemic blood: four had other- wise normal karyotypes and five carried the 17p+ marker or other chromosomal abnormalities (Table 1, Fig. 1). From one to four pairs of terminally associated chromosomes were observed in these metaphases (Table 1). The 13 telomeric associations involved 14 chromosomes in an apparently random manner, although chromosome 22 was most com- monly involved. In a further cell a complete chromosome 22 was attached by the telomeric region of its short arm to the breakpoint Xql3 (t (X;22)). Additional but unidentified chromosomal material was terminally associated with the short arm of a complete chromosome 19 (19p+) in three cells, with the short arm of a complete chromosome 12 (12p+) in one cell and with the long arm of an apparently complete chromosome 20 in two cells (20q+) ( Table 1). a Derivative chromosomes with terminal associations (TA) are fully described in Table 2 b Bone marrow in leukemic remission Cytogenetic studies made on bone marrow aspi- rated when this patient's leukemia was diagnosed showed a predominant abnormal cell line: 46,XX,del(7),t(8;14) (Table 1). Several variants of this cell line were characterized by complete or partial trisomy for the chromosome 1 long arm (lq). In 18 of the 38 metaphases with trisomy for lqll--~lqter (22% of all cells examined), the breakpoint at lqll was in translocation with one of several apparently complete chro- mosomes which provided the centromere of the derivative chromosomes. Thus, the broken region lqll was translocated to the terminal regions of seven other entire chromosomes, Table 2. Descriptions and incidence of derivative chromosomes resulting from translocations of breakpoints in lq with the terminal regions of whole chromosomes in leukemic cells of Patient ...
Citations
... der(21)t(1;21) with 1q21-32 breakpoints was less frequent and has been detected mainly in patients with ALL: 4 of them were diagnosed with B-cell ALL (Raimondi et al 1990;Felix et al., 1998;Andersen et al., 2011;Patterer et al., 2013) and 1 patient with T-ALL (Safavi et al., 2015). In addition, there were sporadic cases with other malignancies: 1 acute monoblastic leukemia (AML-M5) (Chessells et al., 2002), 1 diffuse large B-cell lymphoma (DLBCL), 1 Burkitt lymphoma/leukemia (BL) (Fitzgerald et al., 1984), 1 mycosis fungoides/Sezary syndrome (MF/SS) (Schlegelberger et al., 1994) and 2 multiple myeloma patients (Gabrea et al., 2008;Sawyer et al., 2014). ...
... In the group of patients with 1q21-32 breakpoints , sole anomaly was detected only in 1 T-ALL (Safavi et al., 2015); found in association with t(11;19)(q23;p13) in an infant with B-ALL (Felix et al., 1998), der(19)t(1;19)(q23;p13) in the pediatric B-ALL (Andersen et al., 2011), t(8;22)(q24;q11) in 1 B-ALL (Patterer et al., 2013) and (8;14)(q24;q32) in the BL patient (Fitzgerald et al., 1984). Found in the sideline with der(1)t(1;1)(p36;q21) and -Y/ +8 in infant with AML-M5 (Chessells et al., 2002) and as a part of complex karyotypes in the remaining patients. ...
Unbalanced chromosome translocations involving all or part of the whole long arm of chromosome 1 and the short arms of acrocentric chromosomes are widely reported in human neoplasia. Among them, chromosome translocations between the long arm of chromosome 1 and chromosome 21 have been reported in patients with various conditions, including myeloid malignancies, acute lymphoblastic leukemia, multiple myeloma and lymphomas. © 2018 Atlas of Genetics and Cytogenetics in Oncology and Haematology.
... The cytogenetic data currently available indicate that telomeric associations (TA), i.e., fusion of chromosomes by their telomeres, may contribute to chromosome loss and duplication (Saltman et al. 1993) and the resulting loss of heterozygosity could play a role in tumorigenesis and cellular senescence. Apparent end-to-end fusion of metaphase chromosomes has been observed in human cancer and senescent cells (Benn 1976, Fitzgerald & Morris 1984, Mandahl et al. 1988, Kovacs et al. 1987, Pathak et al. 1988, Saltman et al. 1989, Abruzzo et al. 1991, Zheng et al. 1999, Cottliar et al. 2003. ...
Abstract
PURPOSE:
Telomeric associations (TA) and unstable chromosomal aberration (CA) transmission through M1-M4 metphases (first to fourth division) in gamma-ray irradiated G0 lymphocytes in 2 smokers were examined, since TA in conventionally stained chromosomes were reported earlier as a sensitive cytogenetic marker in mutagen-exposed populations. The purpose of the present study is an extension of our earlier studies on unstable CA transmission through successive mitotic divisions.
MATERIALS AND METHODS:
The bromodeoxyuridine (BrdU) incorporation and fluorescence plus giemsa (FPG) method for M1-M5 metaphase analysis was carried out at 50, 72, 96 h to analyse TA and CA in conventionally and FPG stained chromosomes after irradiation of human blood samples with 3 Gy of gamma-rays. In situ hybridization (ISH) with enzymatic/fluorescence detection was used to analyse radiation-induced aneuploidy and TA. Analysis was carried out on sister chromatid exchanges (SCE) in M2 cells at 72 h and micronuclei (MN) at 24, 50, 72, 96 h.
RESULTS:
TA, corroborated by the absence of acentric fragments, were not detected in conventional/FPG stained/ISH chromosomes. Chromosome 21 aneuploidy was observed. Significant differences in mean frequencies of dicentrics/micronuclei (MN)/SCE with high frequency cells (HFC) were found in smokers after irradiation compared to non-smokers. Higher radiation induced CA in M1 cells were found with extended culture time. Induction of giant cells with mirror dicentrics, tricentrics and rings were found.
CONCLUSION:
TA in conventional or FPG stained metaphase chromosomes is not a sensitive cytogenetic marker for mutagen exposed population screening. Higher radiation induced CA frequencies in M1 cells with extended culture time were indicative of a delay in cell cycle progression of aberrant cells or different lymphocyte subset populations. Bridge-breakage-fusion (BBF) events due to dicentrics may be instrumental in the perpetuation of chromosomal instability. Differential effects were noted in radiation-induced dicentric, SCE and MN frequencies in smokers compared to non-smokers. Heavy smoking could be a confounding variable in chromosome-based biodosimetry and biomonitoring studies. Giant cells may denote a switch to amitotic modes of cell survival, providing additional mechanisms of genotoxic resistance.
PMID: 16782654 DOI: 10.1080/09553000600774097
... Both cytogenetic specimens were collected during lymphocytosis, subjected to identical culture conditions and trisomy 12 was present in each, yet only rearrangements involving telomeric bands were detected in the second specimen. Telomeric associations have been reported in one case of B-CLL (Crossen et al, 1993) and two cases of B-PLL (Fitzgerald & Morris, 1984;Howell et al, 1993). In all three cases, telomeric association was observed in sequential specimens, albeit at reduced levels in the B-PLL cases. ...
... No consistent pattern of telomeric association or rearrangement involving the telomeric region exists in these patients. In the other reported case of telomeric association in B-CLL (Crossen et al, 1993) and one of the B-PLL patients (Fitzgerald & Morris, 1984), the distribution of telomeres involved in associations was random. In this present case and the remaining PLL (Howell et al, 1993), it was non-random. ...
... One B-PLL case (Fitzgerald & Morris, 1984) and the B-CLL case (Crossen et al, 1993) developed solid tumours during the clinical course (adenocarcinoma of the lung and squamous-cell carcinoma of the lung respectively). The development of two solid tumours since diagnosis of B-CLL in this present case seems to fit with a general picture of genetic instability. ...
We report a case of chronic lymphocytic leukaemia (CLL) with telomeric associations and a p53 intronic point mutation. Karyotypic analysis revealed clonal and non-clonal telomeric associations, accompanied by clonal cytogenetic abnormalities and also in isolation. The p53 mutation, which occurred at the invariant base pair -2 of the splice acceptor site in intron 7 resulted in the abolition of correct splicing of exon 7 to exon 8. Multiple aberrant splice products were characterized, all of which differed from wildtype in the DNA binding domain. Fluorescence in situ hybridization demonstrated that the clone retained two copies of the p53 gene and wild-type p53 transcript was detected on cloning of reverse transcriptase polymerase chain reaction (RT-PCR) product, indicating that one wild-type allele remained. However, a plasmid clone with correct splicing at the exon 7/8 boundary, but with a 21 bp deletion in exon 8, was also found at low frequency. This finding indicates clonal evolution, resulting in complete loss of wild-type p53. The intronic point mutation was not present in DNA extracted from cervical tissue indicating that it was a leukaemic phenomenon. This is the first case of an intronic point mutation to be reported in CLL. This mutation led to chaotic p53 expression and, interestingly, occurred in a case showing telomeric associations, a rare phenomenon in B-CLL.
... Three of five aplastic ane-mia patients with excessive telomere loss had acquired an abnormal karyotype, 15 and two types of leukemia with telomeric associations have been reported. 21,22 Moreover, additional chromosome aberrations were found in about 30% autologous HSCT patients, 23,24 and leukemia rarely occurs in donor-derived cells after allogeneic HSCT. [25][26][27] In conclusion, our findings suggest that HSCT for children is safe enough in terms of telomere length, but elderly patients in autologous transplantation or in allogeneic HSCT from elderly donors may develop extremely shortened telomeres. ...
Telomere length of peripheral blood mononuclear cells (PBMCs) from 23 autologous HSCT patients ranging from 4 to 61 years old, and 46 allogeneic HSCT recipients from 6 to 52 years old were studied to confirm whether excessive shortening of telomeres is associated with HSCT. After autologous HSCT, telomere length of PBMCs ranged from 6.8 to 12.0 kb. The comparison between transplanted PBMCs and PBMCs after autologous HSCT showed shortening by up to 1.9 kb (mean +/- s.d.: 0.64 +/- 0.50 kb). There was a difference between autologous HSCT patients and normal volunteers in the slopes of regression lines. After allogeneic HSCT, telomere length of PBMCs ranged from 6.8 to 12.0 kb. Telomeres of recipients were up to 2.1 kb (0.60 +/- 0.468 kb) shorter than those of donors. The slope of regression lines for allogeneic HSCT patients and normal volunteers were parallel. Although all patients were transplanted with more than 2.0 x 10(8) cells/kg, telomere length did not correlate with the number of transplanted cells. There was no significant correlation between telomere length and recovery of hematological parameters. However, three patients with an average telomere length of 6.8 kb after HSCT took a longer period to reach the normal hematological state. Taken together, these data suggest that most HSCTs are performed within the biological safety range of telomeres, while the patients who have telomeres shorter than 7.0 kb after HSCT should be observed carefully for long-term hematopoiesis and the occurrence of hematopoietic disorders.
... It is unclear why TAs are rare in hematological malignancies. To the best of our knowledge, they have only been previously recognized in two cases of B-cell leukemia [6], a case of T-cell ALL [7], and a case of ALL [8]. Nevertheless. ...
... TRF2, for which the gene was cloned recently, may serve to protect chromosomes from end-toend fusions (van Steensel et al. 1998), probably by favoring the formation or stability of D-loops at telomere termini (Griffith et aL 1999). Telomeric fusion, which is rarely seen in normal human cells, occurs frequently in cancer cells (Dhaliwal et aL 1994; Fitzgerald and Morris 1984; Hastie etaL 1990), and in several genetic disorders characterized by hypermutability and/or elevated recombination: Ataxia telangiectasia (Kojis et aL 1989; Kojis et al. 1991 ), Fanconi anaemia, Bloom syndrome, and Xeroderma pigmentosum (Digweed 1993). The G-rich strand of telomere DNA is extended by telomerase, a ribonucleoprotein with reverse transcriptase activity. ...
Genetic recombination is the creation of new gene combinations in a cell or gamete, which differ from those of progenitor
cells or parental gametes. In eukaryotes, recombination may occur at mitosis or meiosis. Mitotic recombination plays an indispensable
role in DNA repair, which presumably directed its early evolution; the multiplicity of recombination genes and pathways may
be best understood in this context, although they have acquired important additional functions in generating diversity, both
somatically (increasing the immune repertoire) and in germ line (facilitating evolution). Chromosomal homologous recombination
and HsRad51 recombinase expression are increased in both immortal and preimmortal transformed cells, and may favor the occurrence of
multiple oncogenic mutations. Tumorigenesis in vivo is frequently associated with karyotypic instability, locus-specific gene rearrangements, and loss of heterozygosity at tumor
suppressor loci — all of which can be recombinationally mediated. Genetic defects which increase the rate of somatic mutation
(several of which feature elevated recombination) are associated with early incidence and high risk for a variety of cancers.
Moreover, carcinogenic agents appear to quite consistently stimulate homologous recombination. If cells with high recombination
arise, either spontaneously or in response to “recombinogens,” and predispose to the development of cancer, what selective
advantage could favor these cells prior to the occurrence of growth-promoting mutations? We propose that the augmentation of telomere-telomere recombination may
provide just such an advantage, to hyper-recombinant cells within a population of telomerase-negative cells nearing their
replicative (Hayflick) limit, by extending telomeres in some progeny cells and thus allowing their continued proliferation.
... To date, JT have been reported in one solid tumor and in 18 various hematologic malignancies, mainly lymphoid disorders such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] As acquired abnormalities, JT are unbalanced, involve non-random donor and recipient chromosome regions, and are associated with disease progression and a usually fatal outcome. In fact, 11 of 16 reported cases with clinical information died shortly after the appearance of JT; four of the five patients who achieved complete remission had had ALL or NHL with t(8;14)(q24;q32). ...
... In fact, 11 of 16 reported cases with clinical information died shortly after the appearance of JT; four of the five patients who achieved complete remission had had ALL or NHL with t(8;14)(q24;q32). [2][3][4][5][7][8][9][10][11][12][13][14][15][16][17] The elucidation of the molecular mechanisms involved in the formation of JT may be of general importance, since their recurrent occurrence as well as their consistent cytogenetic donor breakpoints, suggesting the creation of chimeric proteins or abnormal gene expression, may provide an in vivo model of the origin of translocations. For this reason, we mol-ecularly characterized JT found in a juvenile chronic myelomonocytic leukemia (jCMML), a disease in which unbalanced translocations of 3q have been reported recurrently. ...
... This interpretation is in line with previously reported hematologic malignancies showing JT together with well-known primary changes such as t(4;11)(q21;q23), t(8;14)(q24;q32), t(9;22)(q34;q11) and t(14;18)(q32;q21). 3,4,7,11,12,[14][15][16] However, the correlation between JT and disease progression, poor prognosis and, in the present case, the transformation of an MDS into AML, strongly indicates that JT are of pathogenetic and clinical importance. The donor region in the present case, 3q21, is recurrently involved in translocations and inversions in AML and MDS, eg, inv(3)(q21q26), t(3;3)(q21;q26), t(1;3)(p36;q21) and t(3;5)(q21;q31). ...
Jumping translocations (JT) are characterized by the relocalization of the same part of a donor to several recipient chromosomes. Although JT occasionally are constitutional, most are associated with hematologic malignancies. In such cases, JT usually arise during disease progression and are associated with poor prognosis. Despite its clinical importance, this cytogenetic phenomenon has not been characterized at the molecular level. We have analyzed JT in a juvenile chronic myelomonocytic leukemia that subsequently transformed to an acute myeloid leukemia. Detailed fluorescence in situ hybridization (FISH) analyses showed that the cytogenetically identical donor breakpoint at 3q21 was highly heterogeneous. In fact, more than 10 distinct breakpoints, four of which mapped within YACs, were identified. Analyses of samples during disease progression showed that the breakpoint complexity decreased, indicating clonal selection. Hence, the 3q21 breakpoints displayed a spatial as well as a temporal heterogeneity, revealing that JT are highly unstable, showing great variation in the size of donor segment. The breaks at the recipient chromosomes were mapped within the subtelomeric regions. The general telomere length was not affected and an underlying replication error resulting in microsatellite instability was excluded. We conclude that the emergence of JT is unlikely to cause fusion genes or to affect the expression of genes located in the breakpoint regions. The identification of YACs spanning the breakpoints, ie, YACs 913c7, 937g5, 948c2 and 955g1, may facilitate the isolation of DNA sequences leading to a genetic instability associated with the origin of multiple translocations.
... Recent studies have suggested that abnormal telomeric behavior plays a key role in cancer development. Fitzgeral [1] reported a case of B-cell leukemia and found chromosomal translocation resulting from Tas. The phenomenon has also been observed in tumor cells from a malignant hishocytoma [2] and a case of pre-T-cell acute lymphoblastic leukemia [3] , three cases of cardiac myxoma [4] , and two cases of renal tumor [5] . ...
AIM:To investigate the role of telomeric association in the development of esophageal cancer.
METHODS:Using chromosome R banding technique,telomeric association of chromosome in peripheral blood lymphocytes from 16 untreated patients with esophageal squamous cell carcinoma were observed and 16 healthy adults served as controls.
RESULTS:The teloemeric association frequencies of cell and chromosomes were significantly higher than those of controls(X(2) = 9.56,P 0.05) between the two groups.
CONCLUSION:Chromosomal instability can be initiated by telomeric associations, and sequential chromosome analysis can aid the understanding of the tumor occurrence and progression.
... In some pathologies chromosomes tend to fuse by their telomeres, forming dicentric chromosomes. This phenomena, known as telomeric association (TA), has been reported in various kinds of leukemia [5][6][7], malignant histiocytoma [8], meningioma [9], cardiac myxoma [10], renal tumors [11], Thiberg-Weissenbach Syndrome [12][13][14], squamous cell car-cimona lines [15], senescent and SV-40 infected fibroblasts [16][17][18][19], and in human embryonic fibroblast undergoing senescence [20]. ...
... An unusually high frequency of telomeric associations has been reported in several types of malignant processes [5][6][7][9][10][11]. The results obtained in this study show similarities with those published by other investigators. ...
This study compares the frequency of telomeric associations in the peripheral blood of women suffering breast and cervix uterine cancer with a healthy control group. Two kinds of cultures were developed for each individual: with and without aphidicolin. In the normal cultures, the number of telomeric associations observed was 95.5 times higher in individuals affected by breast cancer and 41.3 times higher in those affected by cervix uterine cancer when compared to the control group (p < 0.001). In the cultures with aphidicolin, higher numbers of altered metaphases were observed in both groups as compared to the control groups (p < 0.001). Statistically significant differences (p < 0.001) could also be observed when comparing telomeric associations between the two types of cancer in both cultures. When we compared individuals affected by breast cancer in both types of cultures statistical differences were found (p < 0.05), and similar results were found in individuals affected by uterine cervix cancer (p < 0.001). The findings suggest that telomeric associations may be reflecting chromosome instability observed in cancer and that this instability behaves differently for various types of cancer.
... It is known that the elderly have Submitted shorter telomeres and more chromosomal abnormalities pertaining to telomeric fusions [10,11]. Tumours are also known to have shorter telomeres and telomeric fusions are also observed in high frequency in these cell lines [12,13]. ...
We have hypothesized that the chromosomal instability observed in scleroderma patients and their family members may result from the loss of long stretches of the telomeric repeat which is found at the ends of all linear chromosomes. We examined the telomere lengths in scleroderma (SSc) patients (n = 43), their family members (n = 182) and in age-matched controls (n = 96) using restriction fragment length polymorphism (RFLP) and chemiluminescent labelled probes. The average loss of telomeric DNA in SSc patients and family members was found to be 3 kb when compared to the controls. This loss was not related to age or the duration of the disease. These results may reflect a genetic predisposition for chromosomal instability in these families, or exposure to a common environmental agent. A wide variety of common environmental agents are known to produce chromosomal aberrations: these include fungicides, pesticides, air pollutants and drugs. Scleroderma-like syndromes may be induced by some of these agents.
