Non-Random Telomere Lengthening at Specific Chromosome Ends as a Novel Clonal Event in Chronic Myeloid Leukemia
Notice bibliographique
Résumé
Abstract It is widely accepted that chromosomal telomere dysfunction caused either by telomere shortening or lesions in the capping machinery is an important factor in carcinogenesis. However, in our recent study using quantitative FISH (Q-FISH), telomere restriction fragment (TRF) analysis and fiber FISH techniques on the measurement of telomere length in 32 cases of chronic myeloid leukemia (CML), we found that telomere lengthening at some specific chromosome ends is apparently a non-random event showing a clonal nature. Methods: TRF: genomic DNA was digested by frequently cutting restriction enzymes. After gel electrophoresis and Southern blotting, the blotted DNA was hybridized to a digoxigenin (DIG)-labeled probe specific for telomeric repeats. A DIG-specific antibody covalently coupled to alkaline phosphate followed by the chemiluminescence detection was used to detect telomere signals. The quantitative measurements of mean TRF length can be reached by scanning the signals on the film and analyzing them with the computer software. Q-FISH: chromosomes on cytogenetic slides were hybridized with a peptide nucleic acid (PNA) telomere probe (Panagene, Korea). The leukemia cells can be traced by the particular chromosome rearrangement presented in the metaphase cells, e.g. t(9;22). The signal intensity, which is proportional to telomere length, of each individual telomere was automatically measured with the software of the imaging system (ISIS 2 MetaSystems, Belmont, MA). The relative telomere length was calculated using the ratio of individual signal intensity to the standard deviation. fiber FISH: fiber FISH was performed with cohybridization of a specific subtelomere probe (with a known size and close to the telomere site of interest) and the telomere probe to the DNA/chromatin fibers preparation on the same slide. Results: The telomere lengthening at short arm of a X chromosome (Xp) was the most frequent event (seen in about 50% of CML cases we studied) in leukemia cells that can be identified by the chromosome 9 and 22 translocation [t(9;22)(q34;q11.2)]. The longest telomere length at Xp end for the CML cases reached 200 kb, which is about 20-fold longer than in normal cells. The other telomeres involved in the non-random lengthening include 18p (7/32), Yp (4/32), 4q (4/32), 5p (3/32), 7q (3/32), and 15p (3/32). Conclusion: While the relationship between the sequence organization for telomere shortening and their function is relatively clear, it has not been well stated if telomere lengthening at specific chromosome ends could be involved in cell proliferation, in maintenance of the genome stability and in evolution of the cancer. Our findings have shown the first evidence that the telomere lengthening at some specific chromosome ends is such a salient clonal event. Further investigation on picking up specific individual telomere lengthening in leukemia cells would greatly aid studies of chromosomal stability, telomerase activity, proliferative capacity and the evaluation of clinical status and thus one can use telomere length as an indicator to follow-up the cancer progression, to evaluate the treatment efficacy and to predict the prognosis in cancer.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».