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We report on 6 patients with tetraploidy or near-tetraploidy acute myeloid leukemia (AML) with double t(8;21) (q22;q22) and review the literature on cases with the same cytogenetic abnormalities. Some common features were revealed by this analysis.
The incidence of in vitro tetraploidy during logarithmic growth in dermal fibroblast monolayer cultures from normals without a family cancer history and affected with heritable colon cancer syndromes, familial polyposis coli (FPC) and the Gardner syndrome (GS) was assayed by (1) examination of metaphase preparations for percentage of tetraploids (4N nuclei); (2) determination of [3H]thymidine incorporation (average cpm/cell); and (3) measurement by flow cytophotometry of the percentage of cells with greater than 4C DNA content. For each monolayer culture assayed, if cell density was standardized, concurrence was observed between the first two assays and with the third assay when done. In cultures of individuals with a low level of in vitro tetraploidy (37 normals without a family cancer history, 9 FPC, and 1 GS patient) incidence of this parameter, as measured by all three assays, was not significantly influenced by variation in cell density. However, in cultures with increased in vitro tetraploidy (17 FPC and 6 GS patients) all three assays revealed an inverse relationship between the incidence of tetraploidy and cell density, i.e., tetraploidy increased with decreasing cell density. Only at cell densities below 4.0 X 10(3) cells/cm2 growth area was increased tetraploidy consistently observed by any of the three assays. Above this density its incidence was indistinguishable in all cultures. The use of these three independent assays (two of which are automated) for the determination of tetraploidy in duplicate subcultures from the same dermal monolayer culture should allow reliable detection of this in vitro expression of some cancer-related genes in extensive human kindreds.
Cancer cells are insensitive to many signals that inhibit growth of untransformed cells. Here, we show that primary human epithelial cells expressing human papillomavirus (HPV) type-16 E6/E7 bypass arrest caused by the DNA-damaging drug adriamycin and become tetraploid. To determine the contribution of E6 in the context of E7 to the resistance of arrest and induction of tetraploidy, we used an E6 mutant unable to degrade p53 or RNAi targeting p53 for knockdown. The E6 mutant fails to generate tetraploidy; however, the presence of E7 is sufficient to bypass arrest while the p53 RNAi permits both arrest insensitivity and tetraploidy. We published previously that polo-like kinase 1 (Plk1) is upregulated in E6/E7-expressing cells. We observe here that abnormal expression of Plk1 protein correlates with tetraploidy. Using the p53 binding-defective mutant of E6 and p53 RNAi, we show that p53 represses Plk1, suggesting that loss of p53 results in tetraploidy through upregulation of Plk1. Consistent with this hypothesis, overexpression of Plk1 in cells generates tetraploidy but does not confer resistance to arrest. These results support a model for transformation caused by HPV-16 where bypass of arrest and tetraploidy are separable consequences of p53 loss with Plk1 required only for the latter effect.
BACKGROUND: Mammalian cells have been reported to have a p53-dependent tetraploidy checkpoint that blocks cell cycle progression in G1 in response to failure of cell division. In most cases where the tetraploidy checkpoint has been observed cell division was perturbed by anti-cytoskeleton drug treatments. However, other evidence argues against the existence of a tetraploidy checkpoint. Cells that have failed to divide differ from normal cells in having two nuclei, two centrosomes, a decreased surface to volume ratio, and having undergone an abortive cytokinesis. We tested each of these to determine which, if any, cause a G1 cell cycle arrest. RESULTS: Primary human diploid fibroblasts with intact cell cycle checkpoints were used in all experiments. Synchronized cells exhibited G1 arrest in response to division failure caused by treatment with either cytochalasin or the myosin II inhibitor blebbistatin. The role of tetraploidy, aberrant centrosome number, and increased cell size were tested by cell/cell and cell/cytoplast fusion experiments; none of these conditions resulted in G1 arrest. Instead we found that various drug treatments of the cells resulted in cellular damage, which was the likely cause of the arrest. When cytokinesis was blocked in the absence of damage-inducing drug treatments no G1 arrest was observed. CONCLUSIONS: We show that neither tetraploidy, aberrant centrosome number, cell size, nor failure of cytokinesis lead to G1 arrest, suggesting that there is no tetraploidy checkpoint. Rather, certain standard synchronization treatments cause damage that is the likely cause of G1 arrest. Since tetraploid cells can cycle when created with minimal manipulation, previous reports of a tetraploidy checkpoint can probably be explained by side effects of the drug treatments used to observe them.
Prenatal diagnosis of a true fetal tetraploidy in direct and cultured chorionic villi: Tetraploidy is characterized by four complete sets of chromosomes (4n= 92). Although it has been frequently reported in spontaneous abortions, tetraploidy is extremely rare in term pregnancy. Most of late surviving patients are diploid/tetraploid mosaics and present severe mental and physical impairment. Up to date, only five tetraploidies were ascertained in the prenatal stage in amniocytes and/or fetal blood lymphocytes. No one has been reported in chorionic villi probably because tetraploidy is generally considered in this tissue as a false positive result due to confined placental mosaicism (CPM) or placental culture artefacts. We report here on a case of tetraploidy detected in chorionic villi because of fetal cystic hygroma. We discuss the reliability of this diagnosis and propose guidelines in the follow-up of tetraploidies detected after chorionic villus sampling (CVS). Thus a misdiagnosis of this poor condition will be avoided at best and an appropriate genetic counseling will be given to the parents.
Tetraploidy and near-tetraploidy are observed infrequently in hematologic malignancies, most commonly seen in cases of childhood acute lymphoblastic leukemia, and are associated with large blast size. Four cases of adult acute myelogenous leukemia (AML) with tetraploid or near-tetra-ploid karyotypes are reported, along with review of the related literature. AML subtypes included M1, M1, M4, and M5b. Tetraploidy was determined cytogenetically and confirmed by image cytometry (DNA index 2.0). The subjective impression of large blast size was confirmed by image cytometry, demonstrating mean blast nuclear areas of 237, 177, 203, and 216 microns2, (mean 208 microns2) in the cases with tetraploidy, compared to a mean of 134 microns2 in 10 control cases of AML with diploid or near diploid chromosome patterns. The clinical course was variable in the four cases reported. When compared with previously published cases, the occurrence of tetraploidy or near-tetraploidy in adult AML, unlike childhood ALL, does not appear to define a distinct subgroup in terms of FAB classification or to carry prognostic implications.
Tetraploidy or near-tetraploidy is a rare cytogenetic abnormality in acute myelocytic leukemia. We report here a case of acute promyelocytic leukemia that showed near-tetraploidy with double der(15)t(15;17) the leukemia relapsed. At diagnosis, cytogenetic analysis failed to reveal any karyotypic abnormality; however, a promyelocytic leukemia-retinoic acid receptor alpha (PML/RARA) fusion transcript of the bcr3-type was detected with reverse transcriptase-polymerase chain reaction analysis, and a single PML/RARA fusion signal was observed with fluorescence in situ hybridization analysis. At the first relapse, the majority of leukemic cells showed pseudodiploid karyotypes with der(15)t(15;17), as well as additional chromosomal abnormalities, and exhibited a single PML/RARA fusion signal. A small fraction of leukemic cells, however, showed near-tetraploid karyotypes with double der(15)t(15;17), as well as some additional chromosomal abnormalities in common with the pseudodiploid clones, and exhibited double PML/RARA fusion signals. At the second and third relapses, leukemic cells with near-tetraploidy and double PML/RARA fusion signals became predominant. The PML/RARA fusion transcript of the bcr3 type was also observed at each relapse. In addition, Southern blot analysis of the RARA gene at diagnosis and at the second relapse showed a common rearranged band. Notably, giant, bizarre, and hypogranular promyelocytes expressing CD2, CD34, and HLA-DR appeared at the first relapse and became predominant at the second and third relapses. These observations indicate that the APL cells with near-tetraploidy and double der(15)t(15;17) clonally evolved from the pseudodiploid leukemic cells and exhibited the bizarre morphology and aberrant surface immunophenotypes.
The prognostic significance of near-triploidy (68-80 chromosomes) and near-tetraploidy (>80 chromosomes) in childhood acute lymphoblastic leukemia (ALL) is unclear. Therefore, we retrospectively evaluated the incidence of and outcome associated with these subtypes of ALL. In 620 children with ALL diagnosed between 1988 and 1999, the leukemic cells were near-triploid (DNA index, 1.50-1.73) in 4 and near-tetraploid (DNA index, 1.79-2.28) in 14. Of 15 patients with B-lineage ALL, 11 (73.3%) had an ETV6-RUNX1 (previously TEL-AML1 and then ETV6-CBFA2) fusion. No differences in age (P = 0.99), leukocyte count (P = 0.99), or immunophenotype (P = 0.99) were observed between patients with near-triploidy and those with near-tetraploidy. Patients with near-triploidy or near-tetraploidy were more likely than those with high-hyperdiploidy (51-67 chromosomes) (n = 159) to be female (P = 0.05) and have T-lineage ALL (P = 0.02), L2 morphology (P < 0.0001), or the ETV6-RUNX1 fusion (P < 0.0001). The median follow-up period was 10.4 years. The 5-year event-free survival estimates (+/- SE) were 75% +/- 19% for patients with near-triploidy, 93% +/- 7% for those with near-tetraploidy, and 84% +/- 3% for those with high-hyperdiploidy. Although near-triploidy and near-tetraploidy are biologically different from high-hyperdiploidy, the favorable outcomes of patients with any one of these abnormalities suggest that patients with B-lineage ALL and a DNA index >or= 1.16 can be included in the low-risk arm of treatment protocols. We cannot make similar recommendations for patients with T-lineage ALL because of the small number of cases (n = 3) in this study.
Liveborn infants with tetraploidy are very rare in human pregnancies and usually die during the first days or months. Seven cases of liveborn infants with tetraploidy have previously been reported. Among them only two 92, XXXX infants survived for longer than 12 months. Here we report on the case of a 26-month-old girl with tetraploidy. The main clinical features of tetraploidy are facial dysmorphism, severely delayed growth and developmental delay. On the basis of molecular studies we discuss the possible origin of the additional chromosome sets in our proband. To our knowledge, this infant is the first reported case of tetraploidy who lived up to 26 months.
Defects in chromosomes or mitotic spindles activate the spindle checkpoint, resulting in cell cycle arrest at prometaphase. The prolonged activation of spindle checkpoint generally leads to mitotic exit without segregation after a transient mitotic arrest and the consequent formation of tetraploid G(1) cells. These tetraploid cells are usually blocked to enter the subsequent S phase by the activation of p53/pRb pathway, which is referred to as the G(1) tetraploidy checkpoint. A human homologue of the Drosophila warts tumor suppressor, WARTS, is an evolutionarily conserved serine-threonine kinase and implicated in development of human tumors. We previously showed that WARTS plays a crucial role in controlling mitotic progression by forming a regulatory complex with zyxin, a regulator of actin filament assembly, on mitotic apparatus. However, when WARTS is activated during cell cycle and how the loss of WARTS function leads to tumorigenesis have not been elucidated. Here we show that WARTS is activated during mitosis in mammalian cells, and that overexpression of a kinase-inactive WARTS in Rat1 fibroblasts significantly induced mitotic delay. This delay resulted from prolonged activation of the spindle assembly checkpoint and was frequently followed by mitotic slippage and the development of tetraploidy. The resulting tetraploid cells then abrogated the G(1) tetraploidy checkpoint and entered S phase to achieve a DNA content of 8N. This impairment of G(1) tetraploidy checkpoint was caused as a consequence of failure to induce p53 expression by expressing a kinase-inactive WARTS. WARTS thus plays a critical role in maintenance of ploidy through its actions in both mitotic progression and the G(1) tetraploidy checkpoint.
Tetraploidy was increased in skin fibroblast cultures grown in the laboratory at the same time under the same conditions and derived from 2 probands with the Gardner syndrome and 9 affected members of one family as compared to that occurring in cultures from 5 relatives by marriage and 10 normals. Tetraploidy was present at the first subculture (2 weeks after the initial biopsy was cultured), and for each line studied the percentage of dividing cells showing tetraploidy remained constant. The relation of the observed tetraploidy to the increased risk of such patients to develop abnormal growths and cancer has not been established. The increased tetraploidy should be of value in identifying the presence of the gene for the Gardner syndrome in high risk families.
Human hereditary tumors in vivo are known to show tissue specificity. Increased endoreduplication with tetraploidy has been shown to occur in cultures established only from tissue containing epithelium (skin and colonic polyps) from patients with the Gardner syndrome. Cultures established from blood (short-term lymphocyte and lymphoid suspension) and connective tissue (subcutaneous tissue, lipoma, mesentery, and sebaceous cyst) from the same patients did not show increased tetraploidy. These observations demonstrated that tetraploidy as an expression of the gene for the Gardner syndrome was cell-specific in vitro and added further evidence that increased tetraploidy could be used for detection of the Gardner gene in families at risk.
Increased in vitro tetraploidy occurred in skin cultures derived from all affected patients and some family members at risk studied in families with heritable colon cancer syndromes (15 of 16 Gardner syndrome families, three Oldfield syndrome families, and four families with heritable colon cancer syndrome without polyposis coli) but was not present in all (one Gardner syndrome family, 16 of 19 familial polyposis coli families, and two Turcot syndrome families). Seven of 97 controls, family members by marriage, showed increased in vitro tetraploidy. None of these seven had a family history of colonic cancer but four had a family history of other solid tumors. Such in vitro studies illustrated that the occurrence of in vitro tetraploidy should be determined in families rather than individuals in order to determine whether all patients clinically affected show increased in vitro tetraploidy and vertical transmission that can be documented.
We report on a 3-month-old girl with unusual facial appearance, short neck with low posterior hairline, wide chest, valvular pulmonic stenosis, abnormal fingernails, and diploid-tetraploid mosaicism (46,XX/92,XXXX in 7.2% of peripheral leucocytes and in 29% of skin fibroblasts). Comparison with 11 previously reported cases with mosaic or complete tetraploidy does not establish an easily recognizable syndrome. However, a malformation pattern is apparent when tetraploidy patients are compared with 14 cases of triploid mosaicism and 44 previously reported cases of nonmosaic triploidy. A history of sex hormone exposure was present in 5 of 11 pregnancies resulting in tetraploidy; this exposure may correlate with the occurrence of tetraploidy in polycystic ovary syndrome and in tumors of the female reproductive tract. The mechanism of dysmorphogenesis involved in polyploidy is considered, including hypotheses of altered nuclear/cytoplasmic ratio, of trophoblastic alteration, of delayed cell division, or of altered autosome/active X chromosome ratio.
In tumorigenesis, aneuploidy is frequently preceded by tetraploidy. Major issues include how tetraploidy arises and how cells can effectively respond to this state. Two recent papers address these issues. Shi and King demonstrate that nondisjunction of chromosomes in mitosis frequently results in tetraploidy through mitotic cleavage failure. Fujiwara et al. demonstrate that p53 null tetraploid cells are highly competent to induce tumors in nude mice. Together, these papers emphasize the unique hazard of tetraploidy and the fact that p53 status has an intrinsic capacity to eliminate tetraploid cells and suppress tumorigenesis. This p53-dependent elimination may represent a checkpoint control.
Massive hyperdiploidy (>50 chromosomes) and tetraploidy (4n) are rare cytogenetic abnormalities in myelocytic malignancies, and their significance is unknown. We report on 11 patients with acute myelocytic leukemia (AML) and two patients with a myelodysplastic syndrome (MDS) with massive hyperdiploidy (10 patients) or tetraploidy (3 patients) seen at our institution over a 12-year period. Eleven patients were male and two were female. Age range was 44-84 years (median, 70 years). Only one AML patient had a previous MDS, and no patient had therapy-related disease. One or more copies of chromosomes 8 and 19 were gained in eight patients each; other frequently gained chromosomes included 13, 15, and 21. Eight patients had structural abnormalities in addition to chromosome gain; del(5q) was most common (five patients). Eleven patients received induction chemotherapy, but only four achieved complete remission. Survival ranged from 1 to 22 months, with a median of 6 months. We conclude that massive hyperdiploidy and tetraploidy are infrequent abnormalities in AML and MDS, are seen primarily in de novo disease in older male patients and are associated with a low remission rate and short survival. Massive hyperdiploidy and tetraploidy define a prognostically unfavorable cytogenetic group in de novo AML.
In vivo expression of human hereditary tumors are known to be tissue specific; in familial polyposis coli the genotype is expressed solely as colonic polyps that become malignant and in the Gardner syndrome as extracolonic connective tissue tumors and related neoplasms in addition to such colonic lesions. In vitro such tissue specificity was also seen in these 2 syndromes. Increased tetraploidy has been observed only in those cultures derived from tissues, which although appearing normal in the patient, were known to undergo malignant transformation in vivo based on clinical phenotypes and family histories: colonic mucosa in familial polyposis coli, skin and colonic mucosa in the Gardner syndrome. Cultures established from tissues known not to show neoplastic growth or from benign tumors (fibromas, sebaceous cysts and lipomas) did not show increased tetraploidy. Increased tetraploidy in cultures established from these 2 syndromes did not identify all cultured cells with either mutant genotype or those cells showing abnormal benign growths in vivo but rather only in those that are known to undergo malignant transformation in vivo in both syndromes. Such observations suggested that in these 2 syndromes there was a population of tetraploid cells, at least in culture, constantly present which may be relevant to the multi-step process of carcinogenesis.
Increased in vitro tetraploidy has been considered an in vitro expression of some cancer-prone genes in dermal monolayer cultures. (Danes BS, Alm T, Scand J Gastroenterol 16, 421-427, 1981; Danes BS, Cancer 48, 1596-1601, 1981). Its occurrence was determined in cultures established from skin biopsies from 112 normals (university students and personnel) whose family cancer histories were known to ascertain its relevance to cancer occurrence based on pedigree data. Of the 40 who gave no family cancer history, one showed increased in vitro tetraploidy (1% of the total studied; 2.5% of those without a family cancer history). Of the 72 with one or more first- or second-degree relatives with a family cancer history, 14 showed this alteration (12.5% of the total studied; 19% of those with a family cancer history). Increased in vitro tetraploidy was found in some normals from families with lung, breast, genital system, and gastrointestinal tract cancers. It may prove ultimately to be relevant to include such in vitro information in medical surveillance and cancer management programs.