Expression of B and T Lymphocyte Attenuator (BTLA) Correlates with CNS Metastasis and Adverse Prognosis in Activated B-Cell Lymphoma and Acute Lymphoblastic Leukemia
Notice bibliographique
Résumé
Abstract Background. The genetic factors that contribute to dissemination and relapse in aggressive lymphomas and acute lymphoblastic leukemia (ALL) are incompletely defined. We tested the hypothesis that shared molecular pathways contribute to drug resistance and metastasis in three distinct types of lymphoid neoplasms: large B-cell lymphoma, primary central nervous system lymphoma (PCNSL, DLBCL) and ALL. Methods. We used a variety of approaches involving high-resolution array-based comparative genomic hybridization, patient-derived cell lines, murine tumor models, diagnostic tumor specimens, and clinical outcome data sets to interrogate the biological significance of candidate mediators of relapse and CNS metastasis. Results. We first tested the hypothesis that genomic aberrations may contribute to the refractory phenotype in aggressive B-cell lymphoma. To pursue this, we compared DNA copy number aberrations in relapsed large B-cell lymphoma that had metastasized to the brain (3 cases, each isolated by resection) with the genomic changes identified in large B-cell lymphoma at diagnosis (15 cases: 12 PCNSL and 3 nodal lymphomas; all DLBCL). We identified a focal recurrent copy number gain at chromosome 3q encoding two candidate proteins: SIDT1, a mediator of microRNA transport, and BTLA, a member of the CD28 superfamily and modifier of both B-cell receptor signaling as well as T-cell responses. Elevated BTLA transcript and protein expression in relapsed specimens was confirmed. We also demonstrated by immunohistochemistry that tumor cell expression of BTLA but not SIDT1 correlated with short overall survival in an independent set of 40 patients with PCNSL treated uniformly with an immunochemotherapy protocol. Using independent databases of systemic DLBCL (n=203 and 69 respectively, Lenz et al. PNAS 2008; Shaknovich et al. Blood 2010), we determined that expression of both BTLA and SIDT1 were significantly higher in ABC compared to GCB DLBCL (p<0.0001) and, in an independent cohort of 73 ABC DLBCL cases, high BTLA expression was associated with a trend towards shorter overall survival (P=0.059). Finally, high BTLA transcript levels, but not SIDT1, correlated with significantly shorter overall survival in both ALL and Ph+ALL in ECOG E2993 (n=215, Geng el al. Cancer Discovery 2012), and with minimal residual disease in COG P9906 (n=207, Harney et al. Blood 2010). In addition, we used flow-cytometry to demonstrate that BTLA was strongly expressed by patient-derived cell lines of primary and secondary CNS lymphoma as well as Ph+ALL. In a murine model of spontaneous CNS metastasis involving patient-derived ABC DLBLC cells, we demonstrated that tumor cell clones that homed to the CNS meninges after flank implantation displayed higher BTLA expression compared to lymphoma cells that metastasized to spleen. Finally, we demonstrated that in a murine model of ALL, genetic deletion of BTLA was associated with impaired ALL cell proliferation and colony formation in vitro. By contrast, BTLA deficiency had no functional consequences in a murine model of CML. Conclusions. Taken together these data suggest for the first time that BTLA expression may contribute to metastasis and CNS progression of activated B-cell lymphoma and to resistance in ALL and Ph+ ALL. Our data suggest that BTLA may not only be a useful biomarker in these aggressive neoplasms, but also a potential therapeutic target. Additional studies are needed to deduce the mechanisms by which BTLA contributes to resistance and metastasis in ABC DLBCL and in ALL. Supported by the Leukemia and Lymphoma Society and the National Cancer Institute Disclosures Rubenstein: Celgene: Research Funding; Genentech: Research Funding.
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 | 0,001 | 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 ».