A Single Nucleotide Polymorphism Of Growth Factor Independence 1 (GFI136N) is a Novel Prognostic Marker For The Progression Of Myelodysplastic Syndrome To Acute Myeloid Leukemia
Notice bibliographique
Résumé
Abstract Myelodysplastic syndromes (MDS) are characterized by disturbances in the development of different blood lineages, which can progress to AML. The knowledge about the factors predisposing the development of AML is sparse. Growth factor independence 1 is a transcription factor regulating the differentiation of myeloid cells. Previously a Single Nucleotid Polymorphism (SNP) of Gfi1, denominated Gfi136N, had been described. This variant is characterized by a SNP leading to the replacement of Serine at position 36 to an Asparagine. This SNP is found in 5-7% of all Caucasians and in 10-15% of all AML patients. We sought to investigate whether Gfi136N could be a novel predictive marker for the development of AML in MDS patients. To this end, we characterized 201 patients with regard to presence of the Gfi136N variant. Patients were recruited from different German centers treating MDS patients, i.e. Essen, Düsseldorf and Dresden. Within this cohort, about 10% were heterozygous for Gfi136N. There was no difference between MDS patients heterozygous for Gfi136N or homozygous for Gfi136S with regard to age, sex, cytogenetic or IPSS score. Presence of Gfi136N significantly increased incidence (Odds ratio 2 fold) and shortened latency to AML progression (around 2 years for Gfi136N heterozygous patients compared to around 6 years for Gfi136S homozygous patients (p=0.001). To further investigate the role of Gfi136N in AML development, we generated mice expressing either the wildtype form of human Gfi1 (Gfi136S) or Gfi136N. We mated these mice with mice expressing the Nup98HoxD13 transgene. Mice expressing Nup98HoxD13 develop a MDS like disease and about 20-30% progress to AML. Mice with Nup98HoxD13 and Gfi136N alleles (n=10) developed AML with a higher incidence (60% compared to 20%) and shorter latency (200 days compared to 340 days) than mice with Nup98HoxD13 and Gfi136S alleles. (n=8, p=0.05) To confirm our finding, we used additional murine AML models resembling human AML cells. MLL-AF9 and AML1-ETO9a are recurrent so called oncofusionproteins, which are charateristic for different human AML subtypes. By retroviral transduction of murine Lineage negative (Lin neg) cells, murine leukemia resembling human AML can be generated. We transduced Lin neg cells from Gfi136S and Gfi136N mice with retroviruses expressing the onocfusionporteins MLL-AF9 or AML1-ETO9a. After seeding in semi-solid medium, transduced Gfi136N cells generated more colonies with a higher cell number than transduced Gfi136S cells (2-4 fold more cells or colonies, depending on the oncofusionprotein, p=0.05). In summary, our data suggest that Gfi136N is a novel predictive marker for AML development among MDS patients which can be recapitulated in mice. To investigate the reason behind this observation, we analyzed lineage negative ckit pos blood cells from Gfi136N or Gfi136S homozygous mice. Genome-wide analysis of histone modification showed that mice expressing the 36N variant display globally higher levels of diMeH3K4 and AcH3K9 activation marks with a significant positive correlation between them. We analyzed the genes, which had a higher level of activation marks in Gfi136N cells compared to Gfi136S. We found that pathways involved in cytokine signaling, hematopoietic lineage development and AML genesis were overrepresented among these genes. Thus we show that Gfi136N might play a crucial role in AML development of MDS patients by inducing epigenetic changes, which promote AML development. Disclosures: Germing: Celgene: Honoraria, Research Funding; Jansen-Cilag: Honoraria; Novartis: Research Funding; GSK: Research Funding; Amgen: Research Funding. Platzbecker:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
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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 | 0,001 |
| 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) | 0,002 | 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 ».