The Transcriptional Profile of PV Displays Limited Similarity to EPO Stimulated Progenitor Cells: Evidence That JAK2 V617F Confers a Novel Program to Malignant Hematopoietic Stem Cells.
Notice bibliographique
Résumé
Abstract Polycythemia vera (PV) is a myeloproliferative disorder characterized by accumulation of mature red cells (RBC). Recent evidence indicates that a mutation of JAK2, V617F, is found in virtually all patients with PV. This allele encodes a constitutively active form of JAK2 and represents a likely pathogenic lesion. JAK2 is required for normal RBC development and is activated by erythropoietin (EPO) during erythroid maturation. Hence the JAK2 mutation may phenocopy EPO stimulation of hematopoietic progenitor cells (HPC). This hypothesis predicts that gene expression profiles of EPO-stimulated normal human CD34+ cells should closely correlate with gene expression found in malignant PV progenitors. We tested this idea using our dataset of human HPC from 8 normals and 9 PV patients and a recently published data set (Ebert et al., Blood 2005) of normal human HPC treated with EPO. In addition, we examined our other data sets to obtain the murine transcriptional program of EPO stimulation, including BaF3-EPO-R cells, HCD-57 cells, fetal liver cells, and phenylhydrazine-primed splenic erythroblasts all treated with EPO. Using low sensitivity direct sequencing we detected the JAK2 V617F mutation in one third of our PV patients and are now using high sensitivity allele-specific PCR to document the mutation in all patients. Further, the gene expression profiles across all of our PV specimens is uniform; hence the PV progenitors in this study are likely representative of JAK2 mutant cells. The human and mouse experiments, pre- and post-EPO treatment, were queried to produce a transcriptional profile of EPO stimulation, i.e. genes that significantly (p≤0.05) changed at least 2x between no drug and EPO treatment after multiple testing correction. A support vector machine selected 31 of 47 EPO- regulated human genes which correctly identified 16 of 17 samples as PV or normal upon leave-one-out cross-validation. This shows similarities exist between normal EPO/JAK2 signaling and PV. However the gene expression signature of EPO stimulated progenitors had very little overlap with the expression profile of PV specimens. Only 3 genes were present in both sets, KLF4, RGC32, SKIP1. Even when the restrictions were eased to a 1.5x change between PV and normal, only 5 genes were common to the PV and EPO sets (KLF4, MCL1, RGC32, SUI1, SKIP1), representing 2.6% of the total. Interestingly, these five genes alone are sufficient to predict EPO treatment in humans and PV status. Analysis of the murine data set yielded an even smaller overlap with PV, 1.1% (2 genes of 177). 38 EPO-regulated murine genes, distinct from the human set, predicted all PV samples correctly and performed with 60% accuracy on cross-validation. We conclude that expression of 5 genes may represent the common action of mutant and wild-type JAK2. The divergence in gene expression pattern between EPO treated cells and PV indicates that the JAK2 mutation in PV progenitors also affects genes distinct from the usual EPO targets during normal hematopoiesis. Genes affected by mutant JAK2 in PV may represent novel therapeutic targets in this disease. We are further testing this hypothesis by expression profiling of normal CD34+ cells expressing the mutant JAK2.
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 | 0,001 |
| 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 ».