Transplantation of Immunodeficient Mice with Chronic Myeloid Leukemia (CML) Cells from Chronic Phase Patients Reveals a Hierarchy of CD34+ Aldehyde Dehydrogenase-Positive Cells with Short- and Long-Term Repopulating Activity and Transient Responsiveness to Imatinib Mesylate in Vivo.
Notice bibliographique
Résumé
Abstract Transplantation of sublethally irradiated NOD/SCID or NOD/SCID-β2microglobulin (β2m) null mice with cells from most chronic phase chronic myeloid leukemia (CML) patients results in the regeneration in the mice of primarily normal human hematopoietic cells. This is due to the usual predominance of normal cells within the most primitive subsets of bone marrow or blood cells in these patients. To date, no markers that allow the most primitive normal and leukemic cells to be differentially isolated from chronic phase CML samples have been identified except those reflecting an increased turnover of the leukemic cells. As an alternative approach to characterizing chronic phase CML stem cells, we have identified particular patient samples that contain predominantly leukemic LTC-ICs and have found that transplants of these samples regenerate a predominance of leukemic cells in both NOD/SCID and NOD/SCID-β2m null mice. To investigate the biological and phenotypic properties of CML cells that have short- and longterm repopulating activity, we transplanted sublethally irradiated NOD/SCID and NOD/SCID-β2m null mice with FACS-sorted subsets of lin- CML cells from 2 such samples and then monitored their output of cells in the bone marrow of the mice for up to 12 weeks. The CD34+CD38+ CML cells produced a rapid but transient wave of mainly myeloid progeny that peaked at 3 weeks whereas the CD34+CD38− cells produced a more delayed but persistent wave of cells in both types of mice that included some lymphoid progeny although the latter represented a markedly reduced proportion of the total relative to the cells produced by normal human bone marrow. These patterns were seen in both recipient genotypes but cell output was enhanced in NOD/SCID-β2m null mice as expected for short-term repopulating cells. In additional studies with 3 patients’ samples, both types of repopulating cells were found primarily in the aldehyde dehydrogenase-positive fraction based on their staining with BODIPY-labeled amino acetaldehyde. To test the feasibility of the CML xenograft model for evaluating novel treatments in vivo, groups of NOD/SCID mice repopulated to high levels with leukemic cells (49±8%) 7 weeks after being transplanted with 3x107 CD34+ CML cells, were injected with 50 mg/kg imatinib mesylate (or not) i.p. twice daily for 10 days. Bone marrow samples obtained from the imatinib mesylate-treated mice 2, 4, 12 and 22 weeks after initiation of this treatment, initially showed a more rapid and greater decline of human leukemic cells (>2-fold as assessed by both FACS and quantitative real-time PCR); however by 5 months after completion of the treatment, the level of human cells in the bone marrow of both the imatinib mesylate-treated and untreated mice was the same. Taken together, these findings demonstrate that the CML clone in chronic phase patients contains a similar hierarchy of short and longterm repopulating cells as is found in normal adult bone marrow, and that the CML repopulating cells have, in addition to their ability to sustain the clone, a greater innate resistance to the toxic effects that imatinib mesylate has in vivo on the majority population of more differentiated CML cells.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».