Niche Requirements of Transient Leukemia Cells in Down Syndrome
Notice bibliographique
Résumé
Abstract Abstract 1753 Background. Young children with Down syndrome (DS; constitutional trisomy 21) have a 150-fold higher risk of developing acute myeloid leukemia (AML). Blast cells are detectable in the peripheral blood of approximately 10% of newborns with DS; these indicate the frequent presence of a preleukemic disorder termed transient leukemia (TL)/transient myeloproliferative disorder (TMD). This disorder of fetal hematopoiesis is triggered by somatic mutations of the hematopoietic transcription factor GATA1 exclusively in the context of cellular trisomy 21. The majority of TL cases undergo spontaneous resolution by unknown mechanisms. In contrast, approximately 1 of 5 cases progress to AML within a defined postnatal window (first 4 years of life). We hypothesized that the resolution of TL results from the absence of essential environmental cues following the developmental transition from prenatal fetal liver (FL) hematopoiesis to postnatal blood cell formation in the bone marrow (BM). We previously observed that primary blasts of human TL lack the proliferative expansion in the bone marrow environment of xenotransplant recipients that is observed for blasts of DS-AML. Consequently, we aimed to identify the signals provided by the FL niche that support the survival and proliferation of human TL cells. Methods and Results. To determine the differential impact of the hematopoietic niche provided by FL and postnatal BM on TL cells, we cultured primary human TL cells on murine stromal cell lines that were derived either from FL (AFT024) or adult BM (MS-5). The absolute number of primary TL cells increased >80-fold during culture on FL-derived stromal cells for 2 weeks. In contrast, BM-derived MS-5 stromal cells supported only a moderate expansion (<10-fold), which was associated with enhanced induction of apoptotic cell death and evidence of partial myeloid differentiation. Direct interaction between TL and stromal cells – acting co-operatively with soluble growth factors – appears indispensable for the maintenance of TL cell survival and stimulation of proliferation. Functional studies identified the very late antigen-4 [VLA-4 (CD49d)]/vascular cell adhesion molecule-1 (VCAM-1) binding partners as putative mediator of this interaction. Furthermore, insulin-like growth factor 2 (IGF-2) supplementation augmented the proliferation of TL cells specifically in the context of the FL niche. Neither IGF-2 alone or in combination with BM-derived stroma promoted expansion of TL cells. Work currently underway aims at identification of additional molecular pathways involved in TL-cell regulation, including elucidating the potential role of Notch signaling in development and maintenance of TL cells. Conclusions. Cooperative signals that are preferentially provided by the hematopoietic environment of the fetal liver support the survival and proliferation of human TL cells. These signals consist of a combination of cell-cell contact, in part mediated by VLA-4/ VCAM1, and soluble growth factors such as IGF-2. The identification and disruption of signaling pathways that are essential for the survival and expansion of TL blasts has the potential to prevent development of AML in children with Down syndrome by targeted elimination of the preleukemic TL clone. Disclosures: No relevant conflicts of interest to declare.
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 | 0,000 |
| 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 ».