Microenvironment Determines Myeloid-Erythroid Lineage Switch in MN1 Leukemia
Notice bibliographique
Résumé
Abstract Transcriptional control of hematopoietic lineage fate relies on the integration of a multitude of intra- and extracellular signals. Interestingly, the leukemic phenotype of MLL-rearranged leukemias has recently been shown also to depend on signals from the microenvironment or secondary mutations. To test whether the microenvironement more generally impacts on leukemic phenotype and whether disruption of cytokine signaling could provide an antileukemic target, we exploited the MN1 model of AML under defined genetically modified microenvironmental conditions. Constitutive expression of MN1 in murine bone marrow rapidly induces myeloid leukemia accompanied by an early-onset severe anemia (Heuser et al. Blood 2007). Here we describe that FLT3 and c-kit signaling direct MN1 expressing cells towards the myeloid lineage whereas loss of both FLT3 and c-kit signaling directs MN1 expressing cells to an immature stage of the erythroid lineage. In addition we identify the N-terminus of MN1 as the critical domain that blocks terminal erythroid differentiation. Based on the finding that murine MN1-expressing bone marrow cell lines can be maintained in FLT3-ligand or low concentrations of stem cell factor (SCF) the requirement of both FLT3 and c-kit signaling for MN1 leukemias was investigated. Cells from FLT3-ligand −/− and c-kit mutated W41/W41 mice were used for transduction with MN1, and wildtype or FLT3-ligand −/− mice were used as recipients of MN1-transformed leukemic cells. Constitutive expression of MN1 in wildtype, FLT3-ligand −/−, or c-kit-deficient cells resulted in leukemic death after 30 to 50 days. Strikingly, constitutive expression of MN1 in W41/W41 cells and transplantation of these cells into FLT3-ligand −/− mice resulted in overt erythroleukemia, whereas expression of MN1 in W41/W41 or FLT3-ligand −/− and transplantation into wildtype recipients, or expression of MN1 in wildtype cells and transplantation into FLT3-ligand −/− cells resulted in myeloid leukemias. Quantitative gene expression analysis of genes associated with erythroid differentiation from leukemic bone marrow demonstrated that Gata-1, but not β-major globin or Klf-1 was significantly upregulated in the erythroleukemias compared to all other myeloid leukemias (p<.001), suggesting that erythroid differentiation was blocked at an early stage. A detailed structure-function analysis of MN1 was employed to identify the domain of MN1 required for the erythroid differentiation block. Deletion constructs of consecutive portions of 200 amino acids of MN1 were functionally characterized for their capacity to induce anemia and leukemia in mice and to block myeloid differentiation in vitro. Interestingly, deletion of the N-terminus of MN1 resulted in declining donor-derived WBC engraftment in mice but increasing donor-derived RBCs in peripheral blood up to 90% over the course of 16 weeks, whereas the other deletions did not show this pattern. Quantitative gene expression analysis of MN1-delN compared to full-length MN1 expressing cells from bone marrow four weeks after transplantation showed a significant increase of Gata-1, KLF-1, and b-major globin expression in MN1-delN expressing cells (p<.001). The ability to block myeloid differentiation was tested by coinfection of bone marrow cells with NUP98HOXD13 and either control vector, full-length MN1 or MN1-delN and determining the IC50 of ATRA. Whereas the IC50 for the control was 0.1 μM, it was >1000 fold higher for both full-length MN1 and MN1-delN, suggesting that the function of MN1 to block myeloid and erythroid differentiation is encoded in different domains of the protein. In summary, loss of FLT3-ligand and impairment of c-kit signaling convert MN1 leukemias from myeloid to erythroid phenotype, but do not change the course of the disease. In contrast, N-terminal deletion of MN1 abrogates the erythroid differentiation block and prevents leukemia, but retains the myeloid differentiation block. Thus, we demonstrate an important role of microenvironmental signals for lineage choice in leukemogenesis.
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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 | 0,001 |
| 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 ».