Biology and Prognostic Value of N-Myristoyltransferase 1 (NMT1) and NMT2 in Acute Myeloid Leukemia (AML)
Notice bibliographique
Résumé
Myristoylation is the post-translational modification of proteins with a 14-carbon fatty- acid by N-myristoyltransferase 1 (NMT1) or NMT2. Myristoylation is key to protein membrane binding and cell survival. Bioinformatics data suggests NMT mRNA expression impacts overall survival (OS) in AML. We characterized NMT protein levels in AML patients. We performed a retrospective and prospective cohort study, including adult patients newly diagnosed with AML in Edmonton from April 2014 until September 2016, excluding acute promyelocytic leukemia. In addition, a small group of control marrow aspirates were obtained. We assayed marrow aspirate or peripheral blood for NMT1/2 protein levels by fluorescence activated cell sorting with intracytoplasmic staining by custom mouse anti-NMT1- Alexa-Fluor-647 or anti-NMT2-FITC, expressed as Mean Fluorescent Intensity (MFI) relative to IgG1k isotype control. NMT1/2 MFI was determined for the bulk blast, CD34+, and CD34+38- blast subpopulations. Clinical data was analysed by t-test or ANOVA. Relapse-free survival (RFS) and OS were dichotomized with a receiver operator curve, followed by a Kaplan-Meier analysis with a log-rank test for significance or univariate and multivariate Cox regression, with p < 0.05 as significant. Censoring, survival, and clinical parameters were defined by European LeukemiaNet (ELN) guidelines and REMARK criteria. Recruitment reached 105 patients. Median age was 67.1 years, with 57 ELN intermediate-risk patients. Median follow-up and OS are 1.54 and 0.95 years, respectively. NMT1 MFI was consistent through all samples. NMT2 MFI was higher in lymphocytes (mean MFI = 3.01 ± 0.08) vs. monocytes (mean MFI = 0.98 ± 0.03, p < 0.001) NMT2 MFI did not vary between AML bulk blast (mean MFI = 1.13 ± 0.03), CD34+ blast (mean MFI = 1.21 ± 0.03), and CD34+38- blast populations (mean MFI 1.22 ± 0.04) (p = 0.145). NMT2 MFI was significantly higher in control CD34+ cells (mean MFI = 1.65 ± 0.11, p < 0.001) and CD34+38- cells (mean MFI = 1.91 ± 0.17, p < 0.001) versus their AML counterparts. NMT2 MFI was significantly higher in AML with the cytogenetic abnormality inv(16) (mean MFI = 1.67 ± 0.05, p < 0.001), and slightly lower with mutated NPM1 (mean MFI = 1.09 ± 0.04, p = 0.004). NMT2 MFI was not associated with ELN risk groups or remission status. (p=0.166, 0.303). NMT2 MFI receiver operator curve analysis for OS in ELN intermediate-risk AML in CD34+38- cells generated a cut-off 1.28 (AUC=0.697, p=0.021) for sensitivity=50% and specificity=80%. Kaplan-Meier analysis was significant with respect to RFS in the CD34+38- population (p = 0.038) and OS in the bulk blast population (p = 0.005). Kaplan-Meier analysis was significant with respect to OS for bulk blast (p = 0.048) and CD34+38- population (p = 0.014) when analyzing the intermediate-risk, age < 65 years patient subgroup. NMT2 was not significant for RFS or OS versus the ELN scheme by univariate or multivariate Cox regression. NMT2 MFI for all intermediate-risk patients was not significant for RFS on univariate Cox regression, but was significant on multivariate regression (p = 0.019). NMT2 MFI for OS in all intermediate-risk patients was significant on univariate Cox regression (p = 0.007) but not significant on multivariate analysis. Age and WBC at diagnosis were used as covariates. We analyzed how NMT1 and NMT2 MFI relate to clinical factors, cytogenetics, molecular abnormalities, ELN risk group, and clinical outcomes in AML. NMT1 was not associated with any of these factors. NMT2 MFI was intermediate in normal hematopoietic stem cells, higher in lymphocytes, and lower in monocytes. This suggests that regulation of NMT2 protein levels may influence early lymphoid/myeloid lineage commitment, possibly by modulation of the T-cell receptor pathway. The cytogenetic abnormality inv(16) showed significantly higher NMT2 MFI, possibly secondary to control of NMT2 expression by the transcriptional regulators RUNX2 and RUNX3. NMT2 MFI was moderately lower in patients with NPM1. NMT2 MFI was not associated with ELN risk group, or achievement of CR with first induction chemotherapy. Higher NMT2 MFI generally predicted worsened outcomes in the ELN intermediate-risk population, with this effect being driven by the CD34+38- blast subsets. This may represent an indirect measure of the stemness of the blast population, and the LSC burden in patients with AML. NMT2 MFI may be a novel biomarker for prognosis in intermediate-risk AML, and further investigation is warranted.
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 | 0,001 | 0,001 |
| 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 | 0,001 | 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) | 0,001 | 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 ».