Deep Phenotypic Characterization of Primitive Stem and Progenitor Compartments Reveals the Cellular Architecture of Aplastic Anemia.
Notice bibliographique
Résumé
Abstract Abstract 2370 Aplastic anemia (AA) encompasses a spectrum of marrow failure disorders that include paroxysmal nocturnal hematuria (PNH), myelodysplastic syndrom (MDS) and acute myeloid leukemia (AML). Despite advances in therapy, approximately a tenth of patients will evolve to severe MDS or AML. A major unresolved question is the nature of the initiating cell that eventually expands during the aplastic phase and gives rise to secondary disease. A critical first step to approach this problem is to characterize the primitive stem and progenitor compartment in AA, taking advantage of the recent advances in phenotypic profiling of primitive human hematopoiesis (Doulatov et al Cell Stem Cell 2012). To this end, we established a 12-parameter flow-sorting scheme for deep phenotypic characterization of the CD34 compartment in AA patients that we used to quantify the gains and losses of all major cellular entities during the aplastic phase. These studies represent the first comprehensive analysis of AA. In 7 out of 10 patients, the proportion of mature myeloid, B cells and NK cells was reduced by greater than 5 fold, whereas the percentage of T cells remained indistinguishable against controls. Within the CD34+CD38-primitive progenitor compartment, the relative number of CD38-CD90+CD45RA- hematopoietic stem cells (HSC) and multipotent progenitors (MPP) reduced. The CD34+CD38+ progenitor populations including common myeloid progenitors (CMP) and megakaryocyte erythroid progenitors (MEP) were either dramatically reduced (>5 fold) or virtually undetectable. Although we hypothesized that absence of phenotypic HSC would result in the absence of its immediate downstream progeny, this was not the case in most of patients. Within the CD34+CD38+ progenitor compartment, MEPs were the most affected population compare to CMPs or GMPs in more than 80% of cases. Interestingly we noticed in 8 of 12 patients, the proportion of granulocyte macrophage progenitors (GMP), defined by FLT3 and CD45RA expression, was unperturbed. To validate whether GMPs from AA patients were functional, we measured the in vitro colony forming capacity of GMP sorted populations. Clonal analyses of these cells in methylcellulose culture showed that these cells have similar potentials and cloning efficiency as normal donor cells. Cloning frequency, size of the clones and number of clones generated in methylcellulose and morphology was also comparable between GMPs from patients and normal donors. We then asked whether these GMPs are the result of a clonal expansion using mitochondrial DNA (MtDNA) analysis. This assay assesses the mutation rate of the D loop region of MtDNA from clones derived from single GMP cells from a patient or healthy donor to gain insight into the diversity within the clones. Our preliminary data suggest that the aplastic anemia GMPs share a closer ancestry compare to GMPs from healthy donor. The in depth quantification of the CD34+ compartment in AA patients that our study provides has directly established that phenotypically defined HSC are profoundly reduced, and this loss has a subsequent impact on downstream components of the hematopoietic hierarchy. The impact of HSC depletion is not a universal loss of progenitors, some progenitors can become overrepresented. Despite the small scale of this study, the overrepresentation of GMP versus other myeloid progenitors in patients with limited clonal heterogeneity suggests that GMP may be a potential candidate for the initiating cell that eventually evolves to MDS or AML. Disclosures: No relevant conflicts of interest to declare.
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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 | 0,000 | 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 ».