Comparing Human Fetal Liver, Cord Blood and Adult Bone Marrow Stem/Progenitor Hematopoietic Cells As Cells of Origin of Human MLL Leukemias
Notice bibliographique
Résumé
Abstract Abstract 2956 Acute leukemias in newborns, children, adults and elderly share the same name, but their genetic, biology and prognosis are significantly different. These differences may be explained by many factors including the nature of the recurrent genetic abnormalities, tolerance to chemotherapy, co-morbidities, etc. One noteworthy potential difference is the cell of origin in which the initial genetic event occurs, which can be a fetal liver, cord blood or adult bone marrow stem/progenitor cell. Genetically engineered mouse models of leukemias and gene expression studies on human acute lymphoblastic leukemias (ALL) suggest that leukemias developing in utero (i.e. in an early ontogenic cell of origin) are biologically distinct from child and adult leukemias. However, direct comparison of human hematopoietic stem/progenitor cells at different stages of ontogeny has not been tested experimentally. Over 70% of infant acute leukemias and 5–10% of adult leukemias exhibit rearrangements of the mixed-lineage leukemia gene (MLL). Therefore, MLL translocations are highly relevant oncogenes to investigate the leukemic potential of the different cells of origin. The MLL-ENL (MLL-MLLT1) fusion gene, from the t(11;19) (q23;p13.3), is one of the most frequent MLL fusion and can occur in infants and adults. It is found in both acute myeloid leukemias (AML) and ALL (both B-cell and T-cell ALL) and we have previously shown that it generates human B-ALL in immunodeficient mice when introduced into lineage depleted human cord blood cells using a retrovirus (Barabé et al, Science 2007). The same experimental design was used to study the cells of origin; CD34+ cells from human fetal liver (FL), cord blood (CB) and adult bone marrow (BM) were infected with either a retrovirus encoding MLL-ENL and an enhanced green fluorescent protein (EGFP) marker gene, or a control retrovirus encoding EGFP only, then injected into sub-lethally irradiated immunodeficient mice. After transduction with MLL-ENL, FL cells generated leukemias in 8/10 mice, CB cells in 6/6 mice and adult BM cells in only 2/7 mice, although four times more cells were transduced and injected. Adult BM cells were very difficult to infect with retroviruses and were clearly not as potent to reconstitute a human graft in immunodeficient mice in comparison to CB cells. All generated leukemias were B-ALL, regardless of the cell of origin. The leukemic phenotype (CD19+, HLA-DR+, CD20-, IgM-, IgG-, CD34 variable) was similar in all three cell types. Mice injected with MLL-ENL-transduced FL and adult BM cells that were not leukemic had a normal human graft but no EGFP cells. The frequency of leukemia-initiating cells (L-IC) was evaluated at 0.2–1% by limiting dilution in secondary mice and no significant differences were observed between the three cell types. Leukemic cells were harvested from the BM of primary mice and cultured in vitro under conditions supportive of both B-lymphoid and myeloid cells. All leukemias were able to grow in vitro and at least one culture derived from each cell type (FL, CB and adult BM) switched to a myeloid phenotype (monocytic morphology with CD33+ and loss of CD19), demonstrating that leukemias derived from all 3 cell types still have myeloid potential. Thus, our results suggest that MLL-ENL can generate leukemia in FL, CB and adult BM CD34+ cells. The lower penetrance of leukemia with adult BM cells is probably due to the difficulty to infect these cells and their limited reconstitution ability. MLL-ENL induces a leukemic program in all three cell types with similar clinical features, cell surface phenotype, frequency of L-IC and conserved bi-lineage potential (B and myeloid). Gene expression profiling and clonality studies are currently performed on leukemias generated from the 3 different cell types. So far, no significant differences between FL, CB and adult BM as cells of origin of MLL leukemias have been identified, suggesting that the nature of the oncogenic hit is probably more important than the ontogenic stage of the cell of origin. Disclosures: No relevant conflicts of interest to declare.
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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) | 0,000 | 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».