Disordered Expression of HIPK Family Members in MDS and AML.
Notice bibliographique
Résumé
Abstract The homeodomain interacting protein kinases (HIPKs) are a group of three nuclear serine/threonine protein kinases originally identified as corepressors for various homeodomain-containing transcription factors. The physiological roles of these kinases are largely unknown, though HIPK1 was reported to be a p53-binding protein and might play a role in tumorgenesis. HIPK2 promotes apoptosis via pathways including p53, transcriptional corepressor CtBP, and Wnt-1 signalling. HIPK2 maps to chromosome 7q32-34 and resides within one of the minimal deleted regions of 7q in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Finally, HIPK3 was first identified as a putative multidrug resistant protein and was reported to be elevated by JNK in prostate cancer cells, thus contributing to increased resistance to Fas-mediated apoptosis. We have utilized Real-Time PCR to investigate the expression of HIPKs in bone marrow from patients with AML (19 patients), MDS (15 patients), chronic myelomonocytic leukemia (CMML, 5 patients), and 11 normal CD34+ mobilized peripheral blood progenitors. The mRNA expression of HIPK1 was higher in AML (P=0.00002), CMML (P=0.02), and MDS (P=0.029) compared to normal. There was also a significant difference in HIPK1 expression between AML and MDS, higher in AML (P=0.009). HIPK2 expression was variable in AML, MDS and CMML patients, while in normal CD34+ cells its expression was consistently low. HIPK3 expression was high in AML compared to normal (P=0.019), but in CMML and MDS its expression was similar to normal. We utilized the AML cell lines HL-60, NB4, and U937 to analyze changes in HIPKs expression during myeloid differentiation. HIPK2 expression significantly increased during ATRA-induced granulocytic differentiation of HL-60 and NB4 cells, but no significant change was seen in Vitamin D3-induced monocytic differentiation of U937 cells. Subgroup analysis of public domain microarray data( Valk et al, NEJM, 2004) indicates that HIPK2 expression is lower in AML patients with -7/-7q compared to other AML patients. We hypothesize that loss of HIPK2 expression contributes to the chemoresistance of -7/-7q AML by impairing normal apoptosis. As an initial test of this hypothesis we have studied the effect of forced expression of HIPK2 on sensitivity of COS-7 cells to daunorubicin, cytarabine and etoposide. COS-7 cells transfected with HIPK2 are more sensitive to daunorubicin with the inhibition rate of growth of 28.31% at 1.6 μg/ml daunorubicin after 48h incubation, while the inhibition rate of COS-7 cell transfected with dominant negative (DN)-HIPK2 (18.80%) was similar to cells transfected with an empty vector (14.96%) and untransfected cells (15.12%) under the same condition of drug exposure. Similar results were found for cytarabine, where the inhibition rate of growth was 17.40% (HIPK2), 9.00% (DN-HIPK2), 6.41% (empty vector), 5.77% (untransfected control). No change of sensitivity was found for etoposide. Conclusions: The anti-apoptotic kinases HIPK1 and HIPK3 are highly expressed in AML, and might have roles in leukemogenesis. HIPK2 shows heterogeneous expression in AML but is underexpressed in AML patients with -7q, and mediates sensitivity to cytarabine- and daunorubicin-induced apoptosis. The possible roles of HIPKs in normal and leukemic hematopoiesis require further investiagtion.
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 | 0,000 | 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) | 0,001 | 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 ».