Abstract B33: Toll-like receptor ligands delay acute lymphoblastic leukemia onset via depletion of pre-leukemic cells
Notice bibliographique
Résumé
Abstract Onset of pediatric acute lymphoblastic leukemia (ALL) depends on the long-term survival and evolution of a pre-leukemic cell population that first arises during fetal development. The detection of chromosomal translocations indicates that about 1% of all newborns harbor early-occurring abnormal cells; however, only 1 in 100 of these infants will progress to leukemia. This reveals that progression to leukemia is not the inevitable fate of these early-occurring abnormal cells. Infection has long been postulated to play a role in the development and progression of pediatric ALL. While epidemiologic studies have implicated exposure to infection as a protective factor, the impact of immune modulation during the pre-leukemic phase has not been reported. In this study, we use the Emu-RET transgenic mouse, which develops fetal-derived B cell precursor (BCP) leukemia, to investigate whether exposure to danger signals associated with infection influences disease progression via changes in pre-leukemic cell survival. Using splenocyte cultures established from pre-leukemic mice, we observed significant depletion of the characteristic pre-leukemic abnormal cells following incubation with a panel of ligands for infection-related pattern recognition receptors. The strongest activity was observed with ligands for Toll-like receptors (TLR) 2 (Pam3), 7/8 (R848), and 9 (CpG), with >75% reduction in pre-leukemic cell number (p<0.01). While IFN-gamma made a contribution to pre-leukemic cell depletion achieved with each of these ligands, the use of IFN-gamma deficient mice revealed that it is absolutely necessary for a significant reduction only with R848 (88% depletion with wild-type, 19% with IFN-gamma deficient cells, p<0.05). To investigate the contribution of direct and indirect pathways to pre-leukemic cell depletion, we purified abnormal cells from pre-leukemic mouse spleens and cultured these cells in the presence or absence of TLR ligands. To date, significant direct cytotoxicity has been observed only with Pam3 (86% reduction, p = 0.0013), while R848 and CpG induce modest direct cytotoxicity. Importantly, however, pre-leukemic cell killing by R848 and CpG was enhanced by the presence of bone marrow from Nod-SCID/gamma common chain-deficient mice, indicating a significant contribution of indirect, lymphocyte-independent killing to the overall depletion of pre-leukemic cells (p<0.0001). Consistent with these in vitro results, we have previously shown that administration of CpG to leukemia-prone mice early in life reduced the size of the pre-leukemic cell population and significantly delayed onset of disease (p<0.0001). While no mice in the control group survived beyond 250 days of age, several CpG-treated mice remained disease free at one year of age and showed no sign of an expanded BCP population at sacrifice. The contribution of IFN-γ to in vivo depletion of pre-leukemic cells following CpG immune stimulation matched that observed in vitro. Our results are the first to deomnstrate that exposure to infection-related danger signals alters leukemia progression through the reduction in pre-leukemic cell viability. These findings provide mechanistic support for the protective effects of early-life infections and suggest novel strategies to eliminate the early-occurring abnormal cells that can give rise to initial disease and relapse. Citation Format: Mario Fidanza, Sumin Jo, Arnawaz Bashir, Stephan A. Grupp, Alix E. Seif, Gregor S. Reid. Toll-like receptor ligands delay acute lymphoblastic leukemia onset via depletion of pre-leukemic cells. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B33.
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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 | 0,000 |
| 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) | 0,002 | 0,001 |
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 ».