Aside from the Allelic Burden of JAK2-V617F, Acquisition of Mutations in Myeloid Gene Panel Is Associated with the Transformation of Myeloproliferative Neoplasm into Secondary AML
Notice bibliographique
Résumé
Abstract Introduction: The discoveries of JAK2-V617F as well as MPL and CARL mutations have greatly clarified the underlying genetics of Philadelphia negative myeloproliferative disease (MPN). Mutation status on these three genes, especially JAK2-V617F, can characterize over 90% of MPN patients. However, the heterogeneity of MPN in terms of its AML transformation and treatment response remains unclear. To assess the difference in mutational status between MPN patients who progress to secondary AML and those who do not, we aim to examine longitudinal samples taken from multiple time points using next generation sequencing. Patients and Methods: Bone-marrow (BM) samples were collected from 19 MPNpatientsfrom2003 to 2012atChonnamNational UniversityHwasunHospital.The diagnosis of MPN was established according to the revised criteria of the World Health Organization.Longitudinal samples were taken at the time of diagnosis and at a follow-up as well as its T-cell fractions (CD+3) isolated from the peripheral blood using MAC separation column.Targeted sequencing was performed using an Agilent custom probe set of a panel of 84 myeloid genes. We multiplexed and sequenced the samples using an IlluminaHiseq2000. Results: The mean on-target coverage for the 57 sequenced samples was 861.4x. We detected a total of 48 somatic mutations in 25 genes in 17 patients (89%) throughout the course of the disease. Five of the 25 genes were recurrently mutated (JAK2, IDH2, ASXL1, SRSF2 and, TP53). As expected, JAK2-V617F was the most commonly observed (15/17 patients). One of the patients without JAK2-V617F carried a MPL mutation and another was triple negative.At the time of follow-up, 12 patients had chronic MPN (11 stable disease and 1 spleen response) withRuxolitinib treatment for a median duration of 373 days (range 255 - 729). Among 7 progressed patients, 5 patients had additional mutation at diagnosis of MPN other than JAK2 or MPL: MPN-13 (DNMT3A and ASXL1), MPN-14 (SRSF2 and IDH2), MPN-15 (IDH2), MPN16 (U2AF1), MPN-17 (IDH2 and SRSF2) as shown in figures. On the other hand, 4/12 non-progressed patients carried additional mutations: MPN-01 (ZRSR2), MPN-05 (ASXL1, CBL, FGR, KMT2D and TET2), MPN-10 (ASXL1, CDH13, EED, EZH2, MN1, NF1 and TRRAP), MPN-11 (FOXP1). In summary, only ASXL1 and JAK2-V617F were recurrently mutated among the non-progressed group. At the time of leukemic transformation, 6 out of 7 patients acquired new mutations: MPN-13 (SETBP1 and TP53), MPN-14 (RUNX1, ASXL1, and IDH1), MPN-15 (TP53 and CASP8), MPN-16 (TP53), MPN-18 (CEBPA), and MPN-20 (ASXL1). In the remaining case (MPN-17), increase of JAK2-V617F VAF was also observed. In summary, TP53 mutation was the most common mutation to acquire by the time of leukemic transformation (n=3). Other mutations acquired by this stage were in SETBP1, RUNX1, IDH1, CEBPA, and ASXL1. We did not observe any significant difference in the allelic burden increase of JAK2-V617F from diagnosis to follow-up between the non-progressed and progressed groups (Figure A). Conclusion: There is no significant difference in mutation burden increase of JAK2-V617F between patients who progressed to secondary AML and patients that did not. Acquisition of mutations other than JAK2-V617F at both diagnosis and at follow-up is associated with the risk of transformation to secondary AML. Mutation profiling using a myeloid gene panel at timed follow-up after MPN diagnosis can be more helpful than monitoring JAK2-V617F status in these patients. Figure Figure. 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 | 0,000 |
| 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) | 0,003 | 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 ».