Microarray Identification of Differentially Expressed Genes in AHI-1- Mediated Leukemic Transformation of Human Cutaneous T-Cell Lymphoma Cells.
Notice bibliographique
Résumé
Abstract Abelson helper integration site 1 (Ahi-1) is a recently identified oncogene which is often the target of provirus insertional mutagenesis in murine leukemias and lymphomas. Ahi-1/AHI-1 encodes a unique cell signaling protein with a SH3 domain, multiple SH3 binding sites, seven WD40 repeats and a number of potential tyrosine kinase phosphorylation sites. Its involvement in human leukemogenesis is demonstrated by gross perturbations in its expression in several leukemic cells lines, particularly in cutaneous T-cell lymphoma (CTCL) cell lines (Hut 78 and Hut 102) where 40-fold up-regulation of AHI-1 transcripts is seen. Hut78 cells are derived from a patient with Sezary syndrome, a common leukemic variant of human CTCL. Interestingly, we have recently demonstrated that aberrant expression of AHI-1 at both RNA and protein levels is found in CD4+CD7− leukemic Sezary cells from patients with Sezary syndrome. Moreover, stable suppression of AHI-1 using retroviral-mediated RNA interference in Hut 78 cells reduces autocrine production of interleukin (IL)-2, IL-4 and tumor necrosis factor-alpha (TNFα) and normalizes their transforming activity both in vitro and in vivo. In an effort to identify genes involved in AHI-1-mediated leukemic transformation in CTCL, Microarray analysis was performed using the Affymetrix Human Genome U133 plus 2.0 Arrays which contains over 47,000 transcripts (54,330 probes). Comparative analysis of six RNA samples from AHI-1/sh4 cells (knockdown of AHI-1) and five samples from Hut 78 and Hut 78 cells transduced with a control vector (RPG) demonstrated that 101 genes (119 probes) were statistically differentially expressed with fold changes > or < 2 at p-values ≤ 0.001, using a DNA-Chip Analyzer (dChip). With the same selection criteria, the Linear Model for Microarray Data (Limma) analysis initially listed 239 genes (283 probes). Once the p-values for these genes were adjusted, using the approach of Benjamini and Hochberg, the list was refined to 27 genes (33 probes). After evaluation of differentially expressed genes selected by both dChip and Limma analyses, 15 up-regulated genes (fold change range: 2.2–11) and 6 down-regulated genes (fold change range: 2.1–8.3) in AHI-1 suppressed Hut 78 cells as compared to control cells, were chosen for further analysis. The expression patterns of these 21 genes identified by Microarray analyses were confirmed by quantitative real-time RT-PCR (fold change range: 6.7 higher to 33.3 lower, p≤0.001). Significant down-regulation of AHI-1 itself (p≤0.001) was confirmed in all six AHI-1/sh4 RNA samples studied. Interestingly, functional grouping of differentially expressed genes in AHI-1/sh4 cells shows several are involved in signal transduction (BRDG1, HCK, and REPS2), cell cycle control (CCNG2, CDKN1C, and PDCD6), cell proliferation and differentiation (BIN1 and MLLT11) and mRNA stability (ELAVL1). Additionally, our observed deregulated expression of NKG7 has also recently been documented in both Sezary syndrome and mycosis fungoides patient samples. Further, candidate tumor suppressor genes (BIN1 and CDKN1C) were found to be highly elevated in AHI-1/sh4 cells where AHI-1 expression is stably inhibited. These findings indicate that we have identified several new differentially expressed genes that may play critical roles in alteration of T-cell signaling in AHI-1 mediated leukemic transformation of human CTCL cells.
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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) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,002 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».