Expression of MLL Fusion Genes in Human Hematopoietic Cells Is Sufficient To Induce Both Acute Lymphoid and Acute Myeloid Leukemia In Vivo.
Notice bibliographique
Résumé
Abstract Malignant transformation involves the acquisition of a series of genetic and epigenetic changes that subvert the normal cellular developmental program and result in the generation of a neoplastic clone with deregulated growth properties. However, in some instances, acquisition of a single oncogenic hit may be sufficient to induce a clinical disease. Studies on identical twins that developed acute leukemias during their childhood have clearly demonstrated that all oncogenes are not equal with some exhibiting greater potency than others. MLL translocations, the most frequent cause of infant leukemias, occur in utero and can be identified on Guthrie cards. Identical twins have a concordance rate near 100% with a short latency, a near synchronous diagnosis and a very poor prognosis, suggesting that MLL leukemias are a single hit disease. In order to test the effects and potency of MLL fusion genes in human hematopoietic cells, we conducted a series of in vivo experiments using retroviruses encoding either MLL-ENL or MLL-AF9. Lineage-depleted cord blood cells were transduced with these viruses then injected into sub-lethally irradiated NOD/SCID mice. 15 out of 16 MLL-ENL mice developed an aggressive human pro-B acute lymphoblastic leukemia (ALL) characterized by the extensive accumulation of immature B cells in the bone marrow and organs in less than 18 weeks. 5 out of 12 MLL-AF9 mice developed the same B-precursor ALL while 2 others developed myelomonocytic leukemia. 5 of the 6 mice injected with MLL-transduced cells did not show evidence of viral integration by PCR. The overall penetrance of leukemia in primary mice with evidence of viral integration was greater than 95%. Transplantation of leukemic cells from primary mice to secondary recipients was able to recapitulate the disease with the same phenotype in a shorter period of time with a penetrance of 100%. Karyotypic analysis of leukemic blasts from primary and secondary mice was normal. Clonal analysis of retroviral integration showed that leukemias generated in primary mice were either monoclonal or oligoclonal (two dominating clones) while the majority of secondary mice had monoclonal disease. At the level of the immunoglobulin (IgH) rearrangements, the B-precursor leukemias were always polyclonal in primary mice, with the presence of the germline rearrangement in addition to other rearrangements. New clones appeared in secondary recipients, suggesting constant rearrangement of the IgH locus. These data also support that a more primitive cell type that had not yet rearranged its immunoglobulin genes was the target of the transforming event, ruling out the possibility that a mature B cell is the target of the transformation. To our knowledge, these results provide the first examples of in vivo models where human hematopietic stem/progenitor cells are transformed into leukemia, recapitulating the features of the human disease. Also, this represents the first reliable in vivo model of B-precursor ALL using MLL fusion genes and highlights species-specific differences in the mechanisms of neoplastic transformation of human and murine cells. The very high penetrance, short latency, normal karyotype and multiple clones that contribute to the disease collectively demonstrate that expression of MLL fusions is sufficient to induce human leukemias in vivo and support the notion that the MLL leukemias are the result of a single genetic hit.
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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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 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 | 0,001 |
| 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 ».