Mechanisms of Resistance to Lenalidomide in Del(5q) Myelodysplastic Syndrome Patients
Notice bibliographique
Résumé
Abstract Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem/progenitor cell malignancies characterized by the presence of dysplastic bone marrow (BM) cells leading to inefficient hematopoiesis in one or more myeloid lineages. The most common chromosomal alteration in MDS, accounting for ~20% of cases, is defined by interstitial deletion of the long arm of chromosome 5, and these cases comprise a distinctive subtype in MDS termed del(5q) . Patients suffering from del(5q) MDS present with anemia, variable neutropenia and thrombocytosis. Patients are blood transfusion dependent, which over time can lead to high mortality due to iron overload. The immunomodulatory drug lenalidomide (LEN) is the treatment of choice for del(5q) patients, achieving transfusion independence and remission in two thirds of treated patients. At the molecular level, LEN cytotoxic activity relies on its binding to the E3-ligase adaptor cereblon (CRBN) selectively leading to CSNK1a protein degradation. Unfortunately, 50% of patients eventually acquire resistance and relapse 2 to 3 years after treatment. Of note, patients at relapse present an increased risk to progress to acute myeloid leukemia. Mutations in the TP53 gene are correlated with resistance to LEN in del(5q) MDS. However, only approximately 20% of patients that become resistant are TP53 mutated. Therefore, there is a medical need to identify drivers of resistance to LEN in del(5q) patients in order to design patient tailored therapies and prevent relapse episodes. To this end, we have collected CD34+ cells from the BM of six del(5q) MDS patients at the time of diagnosis and upon relapse after treatment with LEN and performed whole genome and transcriptome sequencing on these paired samples. By comparing the genome sequencing data at the two time points, we have identified two patients harboring mutations in the TP53 gene: TP53 R273S arises de novo at the resistant stage and TP53 C106Y is existing at diagnosis and expands at relapse. These results are in accordance with previous reports showing strong association of TP53 mutations and resistance to LEN and therefore validate our approach. In addition, we have identified candidate mutations as drivers of the resistant phenotype, which we hypothesize may substitute or cooperate with TP53 mutations, allowing for the malignant del(5q) stem cell survival during LEN treatment and expansion at relapse. Furthermore, RNA-seq data analysis from the paired samples has identified differentially expressed genes shared among all resistant cases and led us to identify novel putative pathways leading to resistance to LEN in del(5q) hematopoietic stem cell. Of note, we did not find any mutation or significant change in the expression of CRBN or CSNK1A1 genes in our cohort of del(5q) MDS patients at relapse, and therefore they do not have a prognostic value for resistance to LEN. The integration of the data obtained in our study will shed light in to the molecular mechanisms leading to resistance to LEN in del(5q) MDS patients and may pave the way for the design of novel and more effective therapies to treat these patients at relapse. Disclosures No relevant conflicts of interest to declare.
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 | 0,001 |
| 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 | 0,001 | 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) | 0,002 | 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 ».