دورية أكاديمية
Phospho-Profiling Linking Biology and Clinics in Pediatric Acute Myeloid Leukemia
| العنوان: | Phospho-Profiling Linking Biology and Clinics in Pediatric Acute Myeloid Leukemia |
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| المؤلفون: | Angela Schumich, Michaela Prchal-Murphy, Margarita Maurer-Granofszky, Andrea Hoelbl-Kovacic, Nora Mühlegger, Ulrike Pötschger, Sabine Fajmann, Oskar A. Haas, Karin Nebral, Nils von Neuhoff, Martin Zimmermann, Heidrun Boztug, Mareike Rasche, Marlies Dolezal, Christiane Walter, Dirk Reinhardt, Veronika Sexl, Michael N. Dworzak |
| المصدر: | HemaSphere, Vol 4, Iss 1, p e312 (2020) |
| بيانات النشر: | Wolters Kluwer |
| سنة النشر: | 2020 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Diseases of the blood and blood-forming organs, RC633-647.5 |
| الوصف: | Aberrant activation of key signaling-molecules is a hallmark of acute myeloid leukemia (AML) and may have prognostic and therapeutic implications. AML summarizes several disease entities with a variety of genetic subtypes. A comprehensive model spanning from signal activation patterns in major genetic subtypes of pediatric AML (pedAML) to outcome prediction and pre-clinical response to signaling inhibitors has not yet been provided. We established a high-throughput flow-cytometry based method to assess activation of hallmark phospho-proteins (phospho-flow) in 166 bone-marrow derived pedAML samples under basal and cytokine stimulated conditions. We correlated levels of activated phospho-proteins at diagnosis with relapse incidence in intermediate (IR) and high risk (HR) subtypes. In parallel, we screened a set of signaling inhibitors for their efficacy against primary AML blasts in a flow-cytometry based ex vivo cytotoxicity assay and validated the results in a murine xenograft model. Certain phospho-signal patterns differ between genetic subtypes of pedAML. Some are consistently seen through all AML subtypes such as pSTAT5. In IR/HR subtypes high levels of GM-CSF stimulated pSTAT5 and low levels of unstimulated pJNK correlated with increased relapse risk overall. Combination of GM-CSF/pSTAT5high and basal/pJNKlow separated three risk groups among IR/HR subtypes. Out of 10 tested signaling inhibitors, midostaurin most effectively affected AML blasts and simultaneously blocked phosphorylation of multiple proteins, including STAT5. In a mouse xenograft model of KMT2A-rearranged pedAML, midostaurin significantly prolonged disease latency. Our study demonstrates the applicability of phospho-flow for relapse-risk assessment in pedAML, whereas functional phenotype-driven ex vivo testing of signaling inhibitors may allow individualized therapy. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2572-9241 |
| العلاقة: | http://journals.lww.com/10.1097/HS9.0000000000000312Test; https://doaj.org/toc/2572-9241Test; https://doaj.org/article/86d754cbc853436596952dc60b4e601cTest |
| DOI: | 10.1097/HS9.0000000000000312 |
| الإتاحة: | https://doi.org/10.1097/HS9.0000000000000312Test https://doaj.org/article/86d754cbc853436596952dc60b4e601cTest |
| رقم الانضمام: | edsbas.7F54C364 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 25729241 |
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| DOI: | 10.1097/HS9.0000000000000312 |