P421: TARGETED DISRUPTION OF HUMAN FLT3 ERADICATES LEUKEMIC STEM CELLS WITHOUT HARMING HEALTHY HEMATOPOIETIC STEM CELLS
Notice bibliographique
Résumé
Background: Resistance to standard chemotherapy is a clinical and biological hallmark of leukemic stem cells (LSCs). The ideal therapy to eradicate leukemia would target the unique vulnerabilities of LSCs while preserving normal hematopoiesis. FLT3 is routinely targeted in FLT3-ITD mutated acute myeloid leukemia (AML), a form of AML especially prone to relapse. Surprisingly, little is known about the importance of FLT3 for LSCs or normal hematopoietic stem cells (HSCs), thus raising questions about how effectively we can or should target FLT3. Aims: Here, we investigated, in parallel, the impact of FLT3 on normal human blood production by HSCs and on leukemia propagation by LSCs. Methods: Using CRISPR/Cas9-mediated gene-editing, we knocked out (KO) FLT3 from HSC originating from human fetal liver, cord blood and adult bone marrow, and from primary AML patient samples with and without FLT3-ITD mutations. The stem cell properties of FLT3-KO and control cells were assessed in xenotransplantation assays, using sub-lethally irradiated NSG mice. Results: We found that normal HSCs from fetal, neonatal and adult human tissues with FLT3-KO retained the ability to form persistent multilineage grafts in immunodeficient recipients, even upon serial transplantation. LSCs from FLT3-ITD mutated AMLs could also engraft upon FLT3-KO but leukemic grafts were lost overtime, suggesting that FLT3 is essential for leukemic persistence and propagation. This dependency was unique to FLT3-ITD AML samples as other types of AML were able to form persistent leukemic grafts upon FLT3-KO. In transcriptomic studies, KO of FLT3 was associated with downregulation of cell cycle checkpoints and DNA repair pathways only in FLT3-ITD mutated AMLs - not in normal HSCs or AML cells without FLT3 mutations. Within in vivo functional studies, FLT3 KO in ITD-mutated AML cells was associated with increased cell cycle progression, DNA damage accumulation and cell death. These data suggest that, specifically in FLT3-ITD mutated AMLs, KO of FLT3 leads to uncontrolled cell cycle progression, DNA damage accumulation and LSC exhaustion that, ultimately, results in the extinction of leukemic clones observed in vivo. Competitive repopulation experiments between normal HSCs and FLT3-ITD mutated LSCs, revealed that grafts were invariably composed of leukemic cells with the mice becoming severely sick in the control group; on the contrary, FLT3 KO group was healthy and the grafts were composed of cells from all blood lineages with normal maturation. Summary/Conclusion: Our study suggests that FLT3 has a dual role in normal and leukemic hematopoiesis: whereas normal blood production can be sustained despite FLT3 disruption, leukemic cells, specifically the highly relapsing form of AML that harbors FLT3-ITD mutations, are extinguished upon FLT3 KO. This evidence places FLT3 as an ideal therapeutic target in AML – essential for LSCs but dispensable for normal HSCs – stressing the need to optimize FLT3 targeting in clinical practice.Keywords: FLT3, Acute myeloid leukemia, Hematopoietic stem cell, Leukemic stem cell
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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) | 0,001 | 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 tête enseignante, 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 ».