Decoding Transcriptomic Landscape and Molecular Pathways in DNAJC21 Deficiency
Notice bibliographique
Résumé
Background: DNAJ homolog subfamily C member 21 (DNAJC21) is a member of the DNAJ heat shock protein 40 family. Biallelic DNAJC21 mutations lead to DNAJC21 deficiency, disrupt ribosome biogenesis and cause a Schwachman Diamond like syndrome. DNAJC21 deficiency causes bone marrow (BM) failure, a risk of evolution to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and extra-hematopoietic symptoms. Due to the limited published data, risk stratification for clonal evolution is currently not possible, and treatments beyond hematopoietic stem cell transplantation (HSCT) are unavailable. Understanding the molecular alterations in hematopoietic stem and progenitor cells (HSPCs) of DNAJC21 deficiency is critical for developing targeted therapies and stratifying the risk for disease progression. Objective: To collect clinical and laboratory data of DNAJC21-deficient patients. To elucidate the transcriptomic landscape and molecular pathways of DNAJC21 deficiency we performed scRNA seq in DNAJC21-deficient BM samples and performed shRNA-mediated DNAJC21 knock down in K562 cell model. Methods: Clinical and laboratory data were collected from 13 patients (9 unpublished and 4 published individuals, respectively). BM samples were collected from 6 DNAJC21-deficient patients and a targeted panel of genes involved in MDS/AML was performed. scRNA-seq was performed on CD34+ cells freshly isolated from the BM of 2 DNAJC21-deficient patients and compared with 2 healthy donors. The role of DNAJC21 was further investigated by reducing its expression in K562 cells using lentiviral shRNA and performing untargeted proteomic analysis. Bioinformatics analysis identified differentially expressed genes, pathways, and cell populations. Results: Data were collected from 13 patients (male:female = 8:5, median age 11 years; age range 1.5-15 years). All patients showed abnormal pancreatic imaging or function. Short stature, developmental delay, skeletal and eye abnormalities were frequently observed (11/13, 10/12, 8/13 and 7/9, respectively). Hypocellular BM was reported in 9/10 patients. Cytogenetic abnormalities were detected in 1 case (46,XY, der(15)t(1;15)(q12;p11)). Five out of 6 patients carried 1 or more somatic TP53 mutations (VAF range 5.3-33%) in the BM samples. P1 (n = 4) and P2 (n = 3) BM biopsy samples revealed progressive decrease in CD3+ T cells with a relative increase in cytotoxic CD8+ cells over time. HSCT was performed in 6 patients due to BM failure. Eleven patients were alive at the time of last follow up. Two patients died due to EBV-associated lymphoproliferative disorder (2.5 months post HSCT) or S. Aureus sepsis, respectively. scRNA-seq analysis revealed distinct transcriptional profiles in HSPCs from DNAJC21-deficient patients. DNAJC21 mutations affect translation and protein synthesis, immune response and metabolism. Notably, enrichment in gene sets involved in ribosome biogenesis emerged with a marked increase in the expression of ribosomal protein genes RPS17, RPL41, and RPL39, as well as the translation elongation factor EEF1G. These dysregulated genes are crucial components of the protein synthesis machinery, suggesting a compensatory response to impaired ribosome biogenesis. A marked decrease in genes involved in proliferation (MKI67, H2AFX, H3F3B, DBF4, UBB, UBC, UBE2S, FOSB, CCNL1) was also observed. Preliminary mass spectrometry analysis of DNAJC21-knockdown K562 cell lines identified several dysregulated pathways, including downregulation of DNA replication and galactose metabolism pathways and upregulation of hematopoietic cell lineage, purine metabolism, and SNARE interactions in vesicular transport pathways. Conclusion: Biallelic DNAJC21 mutations are associated with pancreatic abnormalities and multisystem disorders along with BM failure. The majority of patients harbors TP53 mutated clones with high VAF, whose role in disease evolution and malignant myeloid transformation remains to be elucidated. Biallelic DNAJC21 mutations profoundly impact the transcriptomic landscape of HSPCs, leading to dysregulated ribosome biogenesis and impaired proliferation. Our findings unveil the molecular pathways of BM failure in DNAJC21-deficient patients, highlighting critical pathways and gene sets that could be used as potential biomarkers for disease progression or targeted for therapeutic intervention.
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 | 0,001 | 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 | 0,000 |
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 ».