A single-cell multiomics analysis of IRF4 in mediating treatment resistance in ibrutinib-treated chronic lymphocytic leukemia (CLL).
Notice bibliographique
Résumé
7051 Background: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (ibr) has revolutionized the treatment of CLL, showing efficacy in the majority of patients. Nevertheless, resistance occurs in a subset of patients, often with dismal clinical outcomes. Ibr resistance occurs through several mechanisms, including mutations affecting BTK or PLCG2, or upregulation of alternative survival pathways. We investigated at the single-cell level the molecular mechanisms that underlie ibr resistance in CLL cells and their interactions with non-malignant tumor microenvironment (TME) cell populations. Methods: We retrospectively identified 7 CLL patients with ibr resistance (as second line therapy). Samples were obtained before ibr treatment and at progression. Chromium Single Cell Multiome ATAC + Gene Expression (GEX) (10x Genomics) was applied to a mixture of CD19+CD5+ and CD19- cells to jointly analyze DNA accessibility and gene expression in the same single nuclei of CLL B and TME cells. An average of 4,800 cells (range 2,600-15,000) per sample was retained after QC filtering. Principal component analysis (PCA) was performed on GEX counts. ATAC peaks were called with MACS2, and latent semantic indexing was used for dimensionality reduction. We then computed a weighted nearest neighbour graph, identified clusters using the SLM algorithm and performed cell type assignment with established marker genes. Results: We identified 28 distinct cell clusters, representing CLL B-cells or cell types that constitute the TME, including CD4+ and CD8+ T cells, monocytes, dendritic and NK cells. CLL B-cell clusters were patient and timepoint-specific, while TME clusters were occupied by cells from multiple patients. Five patients showed multiple distinct CLL B-cell clusters pre-treatment or at progression, reflecting cellular heterogeneity within the tumor compartment. Interestingly, some clusters that were dominated by post-treatment CLL B-cells also included cells from pre-treatment samples, suggesting pre-existence of the clone giving rise to the relapse. For each patient, we performed pairwise differential expression between CLL B-cell clusters. Gene ontology analysis revealed increased activation of IRF4 and MHC-related pathways in CLL B-cells at progression compared to pre-treatment in 6 and 4 out of 7 patients, respectively. The elevated IRF4 pathway activity was underpinned by increased chromatin accessibility in IRF4 signature genes. Conclusions: Differential blockade of B-cell receptor signaling by ibr has been reported to downregulate activity of IRF4, a key transcription factor in B-cell activation. Our results suggest that CLL B-cells that are resistant to ibrutinib have re-activated IRF4 activity beyond pre-treatment levels, implying a potential role for IRF4 in ibrutinib resistance.
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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 | 0,001 | 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 ».