A Novel Role for INPP4B in Haematopoiesis and Leukemia
Notice bibliographique
Résumé
Abstract Our studies have focused on characterizing a role for the lipid phosphatase inositol polyphosphate 4-phosphate Type II (INPP4B) in Acute Myeloid Leukemia (AML). Although INPP4B has been reported to antagonize the oncogenic PI3K pathway, and is frequently disrupted in several epithelial cancers, our recent studies provide new evidence for a paradoxical oncogenic role for INPP4B in AML. Our analysis of several AML patient databases led to the discovery that high levels of INPP4B expression were associated with poor clinical outcome, including significantly decreased survival metrics and poor response to chemotherapy. Frequency distribution analysis utilizing a fit of mixture model identified a population of high INPP4B expressers comprising 25% of patients across all the datasets. INPP4Bhigh patients had lower rates of CR compared with their INPP4Blow counterparts (57% vs 74%, respectively; P = 0.01). Accordingly, the mean expression of INPP4B was significantly lower in CR vs NR samples (61.8 ± 2.0 vs 84.9 ± 10.7, P = 0.003). Thus, we have characterized INPP4B as a useful clinical prognostic factor associating with unfavourable outcome in AML. We have since established that INPP4B expression is significantly enriched in human and mouse hematopoietic stem cells (HSC), with an approximate 3-fold higher relative-expression in HSC and MPP compared to common myeloid precursors (CMP), granulocyte-macrophage progenitors (GMP) and multilymphoid progenitor (MLP). We demonstrate compelling evidence that INPP4B protein plays a critical functional role in both human and murine HSC maintenance, using in vivo models of leukemia and Inpp4b-knockout. Inpp4b-knockout mice show a disrupted bone-marrow stem-niche with reduced long-term HSC, HSC and GMP (49.1%, 32.4% and 19.7% lower than wild-type, respectively). To further test the role of INPP4B in HSC we conducted functional assays in vivo. Competitive transplant of bone marrow into lethally-irradiated host mice shows that Inpp4b-knockout cells preferentially reconstitute myeloid blood lineages in the short term, with 78.5% of myeloid cells being Inpp4b-knockout at 16 weeks post-transplant of 1:1 ratio of Inpp4b-knockout to wild-type cells. Targeting proliferating cells with chemotherapeutic agents induces HSC cycling and differentiation to replenish the blood system, and has been used as an indirect measure of HSC functionality in vivo. We then injected mice weekly with 5'-fluorouracil, a non-mutagenic myelosuppressive agent that kills cycling hematopoietic cells, (150mg/kg every 7 days, i.p.) to model repeated hematopoietic injury. We observed a reduced overall survival in Inpp4b-knockout mice compared to wild-type controls, indicating an impaired ability of Inpp4b-knockout HSCs to repopulate the hematopoietic system post-insult. We generated MLL-AF9 leukemic mouse models in Inpp4b-wild type and Inpp4b -knockout bone marrow and determined that Inpp4b is not an absolute requirement for formation of leukemia. In order to better understand the mechanism underlying the role of Inpp4b in hematopoiesis and leukemia we have an undertaken an unbiased -omics approach to identify key changes associated with Inpp4b-loss in stem and progenitor cells. We have performed quantitative-proteomics and next-generation sequencing on HSC, CMP, GMP and MEP populations. We have also investigated altered signalling dynamics associated with Inpp4b-loss- quantifying phospho-signalling changes in stem-enriched cell populations by means of high-dimensional single-cell mas-cytometry. Based on our current data, we hypothesize that INPP4B plays a critical role in HSC maintenance and contributes to worse leukemia. We further hypothesise it is this stem-related function of INPP4B that is responsible for the poor therapy response observed in patients with elevated INPP4B. Given the aging population, and the association of AML and age on prognosis, our success has the potential to have an impact on an ever-growing number of patients. Disclosures No relevant conflicts of interest to declare.
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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 | 0,001 |
| 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 | 0,001 |
| 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 ».