Loss of MiR-143 and MiR-145 Inhibits Hematopoietic Stem Cell Self-Renewal through Dysregulated TGFβ Signaling
Notice bibliographique
Résumé
Abstract Myelodysplastic syndromes (MDS) are a collection of hematopoietic malignancies in which genomic abnormalities within the hematopoietic stem cell (HSC) compartment results in dysplasia of the marrow cells and ineffective hematopoiesis. As a result, the primary cause of mortality in these patients is eventual bone marrow failure although MDS patients also have a significantly increased risk of transformation to acute myeloid leukemia (AML). The most common karyotypic change in MDS is an interstitial deletion of the long arm of chromosome 5, del(5q) MDS. Patients with an isolated interstitial deletion of chromosome 5q are referred to as having 5q- syndrome. Mapping of the commonly deleted region (CDR) within 5q- syndrome has identified a 1.5-megabase region on band 5q32. MicroRNA (miRNA) -143 and -145 are located within the CDR of del(5q) MDS and have been implicated in the pathogenesis of the disease. However, their functional role in myelodysplastic syndromes has not been well studied. To investigate the role of miR-143 and miR-145, we utilized a gene-targeted mouse model containing deletion of miR-143 and miR-145. Here we show that mouse marrow lacking miR-143 and miR-145 have a decrease in short-term repopulating HSC and progenitors of the myeloid lineage by flow cytometry, as well as of hematopoietic progenitor activity using colony forming assays. Additionally, we performed a limiting dilution assay of miR-143-/-145-/- bone marrow and observed significantly fewer functional HSCs compared to wildtype marrow. To explore the molecular mechanism behind this defect, we performed Ingenuity Pathway Analysis of the predicted targets of miR-143 and miR-145. We identified the transforming growth factor-beta (TGFβ)-signaling pathway as a common target of these two miRNAs. Gene Set Enrichment Analysis of del(5q) using mRNA expression of MDS patient CD34+ marrow cells show an enriched TGFβ-signature compared to healthy controls. In addition, the defect in hematopoietic progenitor activity in miR-143-/-145-/- marrow can be rescued by inhibiting Smad3 using the chemical inhibitor SIS3. We validated the TGFβ pathway adaptor protein, Disabled-2 (DAB2), as a target of miR-145 and show that TGFβ signaling is activated upon loss of miR-145 or enforced expression of DAB2. Enforced expression of DAB2 in mouse marrow is able to recapitulate many of the features of miR-143-/-145-/- mice. DAB2 overexpressing marrow formed significantly fewer colonies in progenitor assays, and in competitive transplants, vector-transduced marrow was able to out compete DAB2-overexpressing marrow in both primary transplants as well as in secondary limiting dilution assays. Interestingly, compared to wildtype mice, aged miR-143-/-145-/- mice showed decreased hemoglobin and platelet counts with elevated white blood cell counts. This phenotype was also observed in a subset of mice with enforced DAB2 expression where a proportion of mice developed a transplantable myeloproliferative disorder. Together, our data identifies a role for miR-143 and miR-145 in the pathogenesis of del(5q) MDS where their loss results in a defect in HSC activity. We observe that the TGFβ signaling pathway is activated in patient marrow and we validate DAB2 as a direct target of miR-145. We provide evidence that the defect observed in miR-143-/-145-/- marrow is mediated in part by DAB2 where its enforced expression leads to a defect in HSC self-renewal but contributes to myeloproliferation. Disclosures Karsan: Celgene: 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 | 0,000 |
| 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 ».