CD47-Sirpα Interaction Modulates Homing and Engraftment of Human Acute Myeloid Leukemia Stem Cells in Mice.
Notice bibliographique
Résumé
Abstract Abstract 476 Introduction: A large body of work has shown that acute myeloid leukemia (AML) clones are hierarchically organized and maintained by leukemia initiating cells (AML-LSC). However, little is known about molecular regulators that govern AML-LSC fate. Using the non-obese diabetic (NOD)–severe combined immunodeficiency (SCID) xenotransplantation model, our group recently found that CD47-SIRPα protein interaction is essential for repopulation of normal hematopoietic stem cells (HSC) in mice (Takenaka et al, Nat Immunol 2007). The NOD background conferred the best support for human engraftment, whereas mice with other polymorphisms of Sirpa could not be engrafted (i.e. NOD.NOR-Idd13.SCID). CD47 on human AML contributes to pathogenesis by inhibiting phagocytosis of leukemia cells through CD47-SIRPα interaction (Jaiswal et al, Cell 2009). CD47 is increased on human AML LSCs compared to normal HSCs, and high levels of CD47 are associated with poor patient outcome (Majeti et al, Cell 2009). This indicates that CD47 may function as an important molecular regulator of AML-LSC fate through communication with SIRPα protein expressed on cells of the innate immune system. Results: Consistent with published results, we observed increased CD47 expression in primary AML cells compared to normal cord blood cells. We next investigated the functional relevance of CD47 for AML-LSCs by xenografting primary human AMLs into NOD.SCID and NOD.NOR-Idd13.SCID (Idd) mice. Following intravenous (i.v.) transplantation, none of three primary human AML samples could engraft Idd mice while robust engraftment in NOD.SCID mice was observed, consistent with our previous data using normal human HSCs. When the same samples were transplanted intrafemorally (i.f.), 2 of 6 Idd mice showed engraftment in the injected femur but no engraftment in other bones or the spleen; evidence of the latter is linked to stem cell function. To assess the role of innate immunity, we pre-treated mice with antibody against murine CD122 which depletes host natural killer (NK) cells and macrophages. Engraftment in the injected femur was observed in NOD.SCID mice (43/43) for all 10 AML samples tested, and interestingly in 31 of 42 Idd mice (8/10 AML samples tested), with similar engraftment levels (Idd 37.4±6% vs NOD.SCID 53.8±5%, p=0.33). As expected, NOD.SCID mice supported migration to non-injected bones (38/43 mice, 10/10 AML samples tested). In contrast to results obtained in the absence of anti-CD122 pre-treatment, engraftment in non-injected bones was now detectable in 8 of 42 Idd mice (2/10 AML samples tested), pointing to improved migration of AML-LSCs following depletion of NK cells and macrophages. However, the engraftment level in non-injected bones was significantly lower in Idd compared to NOD.SCID mice (2.4±4% vs 63.2±6%, p=0.001). Moreover, AML-LSCs were unable to repopulate the spleens of Idd mice. Homing assays revealed decreased homing to BM and spleen 16 hours following i.v. injection in Idd compared to NOD.SCID mice. Conclusion: Our results support the hypothesis that CD47-SIRPα interaction is critical for engraftment of AML-LSCs. Attenuation of CD47-SIRPα interaction (as in Idd mice) leads to decreased engraftment ability of AML-LSCs. Enhancement of engraftment in the injected femur and in some cases migration to other bones in Idd mice following anti-CD122 treatment is likely mediated through interference with cells of the innate immune system. Interruption of CD47-SIRPα signaling through targeting of either CD47 or SIRPα provides a potential therapeutic approach for eradication of AML-LSCs. Disclosures: Dick: Roche: Research Funding; CSL Ltd: Research Funding.
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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 ».