UM171 Expands Immature Bone Marrow CD34+ Cells of Patients with Telomere-Biology Disorder
Notice bibliographique
Résumé
Introduction: Telomere-biology disorders (TBD) are caused by germline defects in genes involved in telomere maintenance, resulting in excessive telomere shortening and limited cell proliferation. Clinically, TBD corresponds to a spectrum of phenotypes associated with bone marrow failure and lung and liver diseases. It also is associated with a higher predisposition to cancer, including myelodysplastic syndrome and acute myeloid leukemia. Patients with affected hematopoiesis usually present cytopenias and hypocellular marrow with reduced numbers of CD34+ cells to maintain adequate hematopoiesis. Treatment options for marrow failure patients are restricted. The most effective approach is allogeneic bone marrow transplantation, but the availability of compatible donors and complications of the conditioning regimen limit it. Alternatively, androgens may alleviate cytopenias, but their long-term effectiveness may be restricted (Townsley et al. 2016; Clé et al. 2023; Pagliuca et al. 2024). There is no evidence that TPO agonists have any effects in these cases. Fares et al. (2014) demonstrated that the small molecule UM171 expands the CD34+ cell subpopulations from human umbilical cord blood with superior engraftment potential and better clinical outcomes (Cohen et al. 2022). UM171 is a pyrimido-indole derivative that activates the CRL3KBTBD4 E3 ubiquitin ligase, targeting the CoREST1 complex and maintaing the epigenetic landscape required for hematopoietic stem cell properties (Chagraoui et al. 2021). Here, we assessed the potential of UM171 to expand the hematopoietic progenitor and stem cell (HPSC) compartment of patients with TBD and marrow failure. Methods: Bone marrow samples were collected from six patients diagnosed with TBD (four females; median age, 39.5 years; range, 16 to 56 years). All patients had short telomeres and a hypocellular bone marrow. Two patients were diagnosed with aplastic anemia, three with cytopenias, two with pulmonary disease, and one with liver cirrhosis. Heterozygous TERT mutations were found in four patients, TERC mutations in two, RTEL1 in one, and POT1 in one, all in heterozygosis. Bone marrow samples from six healthy controls (all males; median age, 27,5 years; range, 24 to 71 years) were studied as controls. CD34+ cells were enriched using immunomagnetic labeling with human CD34 microbeads and a magnetic separator. Cells were cultured for 7 days in ACF medium supplemented with cytokines that support HSC expansion and UM171 or DMSO (control). To assess the capacity of the cultured cells to generate hematopoietic progenitors, 1,000 cells/mL were resuspended in methylcellulose in triplicate. After 14 days, the colonies were counted and classified according to morphology. Results: Patients had fewer CD34+ cells in the bone marrow compared to controls (median, 0.68% vs. 1.69%, respectively; P=0.03). After a 7-day expansion, the percentage of CD34+ cells was higher when treated with UM171 (UM171, 56.9 ±5.7% vs. DMSO, 34.9% ±6.5% [median ±standard error] n=6; P=0.003). The cell surface EPCR is a marker for the purification of the HSPC compartment, and the CD34+EPCR+ subpopulation was increased after UM171 treatment (UM171, 3.35±1.1% vs. DMSO, 0.2% ±0.1%; n=6; P=0.03). UM171-treated cells gave rise to more progenitor cells, as observed by the CFU assay (UM171, 142±18 vs. DMSO, 94%±9; n=4; P=0.01). No significant telomere attrition was observed with the expansion. We also analyzed the appearance of abnormal clones during expansion by NSG for myeloid-malignancy somatic mutations and chromosomal abnormalities by single nucleotide polymorphism array (SNP-array) in CD34+ cells from three patients and two healthy controls. No abnormal clones were observed after UM171 expansion. Conclusions: Our results reveal UM171 as a potent HSPC expander in TBD patients. Our data suggest that UM171 may enhance the ex vivo production of HSPC from TBD patients. These findings contribute the understanding of the effect of UM171 on patient-derived cells.
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) | 0,004 | 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 ».