The Exportin, CSE1L, Regulates Ribosome Biogenesis and Is a Selective Dependency in Childhood and Young Adult Acute Myeloid Leukemia
Notice bibliographique
Résumé
Nuclear transport receptors, termed importins and exportins, regulate protein transport through the nuclear pore. Although genetic alterations in the nuclear pore complex are more common in young AML patients (e.g., NUP98 rearrangements), nucleocytoplasmic transport has not been studied extensively in childhood/young adult AML. We compared the expression of genes associated with nucleocytoplasmic transport in young (<40 years; mean age 27 in BeatAML & 29 in TGCA) and older (>40 years, mean age 64 in BeatAML & 61 in TCGA) AML patients and identified enrichment of nucleocytoplasmic transport pathways in childhood/young adult vs older AML (BeatAML P=2.43e-3, FDR=0.01, TCGA P=2.39e-4, FDR=3.46e-3). Young patients with nucleoporin (NUP) rearrangements had high expression of nucleocytoplasmic transport genes, but this pathway was also upregulated in young patients without NUP rearrangements, compared to older patients. Of the nucleocytoplasmic genes, CSE1L was the top differentially expressed exportin in young vs older AML patients. CSE1L is an exportin with a role in recycling importin alpha proteins. Recently, CSE1L was found to export circular RNA. Its function in childhood/young adult AML is unknown. By immunoblotting, we confirmed increased expression of CSE1L protein in childhood/young (n=10, mean age 23) vs older (n=10, mean age 77) AML. CSE1L mRNA expression predicted outcome exclusively in young patients (<40 years), where increased CSE1L predicted for decreased remission rates (P=0.027), event free survival (P <0.0001) and overall survival (P<0.0001), but was not predictive in older patients (TARGET, Beat AML) . To further understand the dependency of childhood/young adult AML on CSE1L, we knocked down the gene with shRNA in AML cell lines derived from young patients (NB4, MV4-11, THP-1) and TEX cells, derived from transducing cord blood with a high-risk pediatric fusion, FUS-ERG. CSE1L knockdown reduced AML growth, viability and clonogenicity. We confirmed loss of AML viability and clonogenicity using CSE1L CRISPR knockout. Gene dependency scores indicated a greater reliance on CSE1L than XPO1 in young AML cell lines (P<0.0001). Knockdown of CSE1L in primary AML cells from a young chemo-refractory patient with high CSE1L expression, reduced leukemic engraftment into mouse marrow. CSE1L depletion also reduced AML engraftment in secondary transplants, demonstrating its essentially for leukemic stem cells. In contrast, knockdown of CSE1L did not impair engraftment of normal human hematopoietic cells into mouse marrow. To understand the function of CSE1L, we interrogated a BioID database (PXD007976) and identified proteins that interact with CSE1L. Among the CSE1L interactors, ribosome biogenesis was the top biologic process identified. We validated the interaction with ribosome biogenesis proteins and BioID hits, RRS1 and RPL29 using Co-IP and proximity ligation assay. Knockdown of CSE1L in TEX cells led to nuclear accumulation of RPL29 and a reduction in cytoplasmic RPL29 (3.3 fold). Using a GFP reporter assay that incorporates into the large ribosomal subunit precursor (pre-60S), we induced depletion of CSE1L and confirmed decreased cytoplasmic RPL29-GFP. Pre-ribosome export is closely coordinated with rRNA maturation and pre-ribosome assembly. CSE1L knockdown decreased the expression of pre-60S and ribosome biogenesis pathways and quantitively reduced rRNA transcription rates by PCR (3 fold), consistent with a role for CSE1L in large ribosome subunit export and ribosome biogenesis. Given increased CSE1L expression in young patients and its role in ribosome biogenesis, next we investigated ribosome biogenesis in AML patients. Ribosome biogenesis pathways were the top differentially expressed gene sets in young vs older AML patients (BeatAML P=1e-10, FDR=7.9e-8, TCGA P=2.34e-4, FDR=3.4e-3). Expression of ribosome biogenesis pathways positively correlated with expression of the nucleocytoplasmic transport pathway. In summary, nucleocytoplasmic transport and ribosome biogenesis are upregulated in young AML patients. The nuclear exportin, CSE1L, is a regulator of ribosome biogenesis and its depletion leads to impaired ribosome biogenesis and leukemic cell death in childhood/young adult AML. Thus, our findings reinforce growing evidence that childhood and older adult AML are fundamentally different diseases, driven by different biologic processes.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,001 | 0,001 |
| 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) | 0,001 | 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 ».