INPP4B is a Biomarker of Poor Prognosis in AML Which is Associated with EVI1 Overexpression and a LSC Signature
Notice bibliographique
Résumé
Abstract Acute myeloid leukemia (AML) is a highly heterogeneous cancer of the bone marrow. To better understand leukemogenesis and improve predictors of patient response to chemotherapy and overall survival (OS), we recently examined the role of inositol polyphosphate-4-phosphatase, type-II (INPP4B) in AML. Normally, INPP4B plays a role in PI3K/Akt signaling by regulating phosphorylation of phosphoinositides (PIs), critical membrane-bound second messenger molecules, by dephosphorylating the 4'-position of PI(3,4)P2 to generate PI(3)P. Because PI(3,4)P2, like PI(3,4,5)P3, is necessary for the activation Akt, INPP4B was first hypothesized and demonstrated to be a tumor suppressor protein, akin to PTEN, in several cancers including breast, prostate and ovarian. Recent work however, including our own study, has demonstrated a paradoxical tumor-promoting role of INPP4B in AML and estrogen receptor positive (ER+) breast cancer. Specifically, we demonstrated that INPP4Bhigh AML patients (25% of patients) had significantly shorter OS, lower response to induction therapy, and shorter event-free survival. Furthermore, INPP4B expression was found to be an independent prognostic marker for OS in AML outperforming FLT3-ITD and NPM1 mutation status. Overexpression of INPP4B in several AML cell lines results in enhanced colony formation potential, chemotherapy drug resistance, and increased proliferation. Though this previous work has shown that INPP4B plays a significant role in AML, it remains unclear why INPP4Bhigh AML differs from INPP4Blow AML, and what causes its upregulation. To address this question, we interrogated gene expression data from three independent datasets (n=942) to identify genes with differential expression between INPP4Bhigh and INPP4Blow AML. Gene expression analysis revealed that INPP4Bhigh AML was associated with differential expression of 233 genes. High INPP4B expression was associated with higher expression of genes related to the hematopoietic lineage, PI3K-Akt signaling, Jak-STAT signaling and ECM-receptor interaction pathways. Specifically, INPP4Bhigh AML has significantly higher expression of leukemic stem cell signature (LSC) genes CD34, RBPMS, GUCY1A3, KIAA0125, SOCS2, SPINK2, HTR1F, PPP1R16B, EVI1 (MECOM), DAPK1, BAALC, ABCB1, and PRKCH. Furthermore, INPP4B was found to be co-expressed with anti-apoptotic genes of the BCL2 family, namely BCL2 and BCL2L1. Further analysis revealed that INPP4B was co-expressed with the transcription factors EVI1, GATA2, NFATC2, ZEB1, GATA3 and ETS1, all of which having predicted binding sites within the INPP4B promoter region. Due to the observed enrichment of hematopoietic lineage/LSC genes in INPP4Bhigh AML, we wanted to validate the potential role of the EVI1 transcription factor in regulating INPP4B expression. Chromatin immunoprecipitation was used to demonstrate that EVI1 binding was enriched in the INPP4B promoter region of both EVI1high OCI/AML-4 and OCI/AML-6 cell lines. In addition, retroviral overexpression of EVI1 in EVI1low U937 cells resulted in subsequent upregulation of INPP4B transcript levels. Moreover, shRNA mediated knockdown of EVI1 in EVI1highOCI/AML-4 and UCSD-1 cells resulted in downregulation of INPP4B expression. Overall, our analysis reveals that INPP4Bhigh AML is characterized by upregulation of genes related to the hemotopoietic lineage, and LSC signature - consistent with the in vitro colony formation phenotype seen in INPP4B overexpressing AML cell lines. Furthermore, we demonstrate that one of the hematopoietic stem cell genes, EVI1 is a potentially key regulator of INPP4B expression in AML. Disclosures Jain: Roche Canada: Research Funding.
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 | 0,001 |
| 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 ».