Hoxa9 and Meis1 cooperatively induce addiction to syk signaling by suppressing miR-146a in acute myeloid leukemia

The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Ho
The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
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Metadaten
Author:Sebastian Mohr, Carmen Döbele, Federico Comoglio, Tobias Berg, Julia Beck, Hanibal Bohnenberger, Gabriela Alexe, Jasmin Corso, Philipp Ströbel, Astrid Wachter, Tim Beißbarth, Frank Schnütgen, Anjali Cremer, Nadine Hätscher, Stefanie Göllner, Arefeh Rouhi, Lars Palmqvist, Michael A. Rieger, Timm Schroeder, Halvard-Björn Bönig, Carsten Müller-Tidow, Florian Kuchenbauer, Ekkehard Schütz, Anthony R. Green, Henning Urlaub, Kimberly Stegmaier, R. Keith Humphries, Hubert Serve, Thomas Oellerich
URN:urn:nbn:de:hebis:30:3-437282
DOI:http://dx.doi.org/10.1016/j.ccell.2017.03.001
ISSN:1878-3686
ISSN:1535-6108
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=28399410
Parent Title (English):Cancer cell
Publisher:Cell Press ; Elsevier
Place of publication:Cambridge, Mass. ; New York, NY
Document Type:Article
Language:English
Date of Publication (online):2017/06/29
Date of first Publication:2017/04/10
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/06/29
Volume:31
Issue:4, e11
Pagenumber:26
First Page:549
Last Page:562
Note:
© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
HeBIS PPN:427891132
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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