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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 Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive...

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Main Authors: Mohr, Sebastian (Author) , Doebele, Carmen (Author) , Comoglio, Federico (Author) , Berg, Tobias (Author) , Beck, Julia (Author) , Bohnenberger, Hanibal (Author) , Alexe, Gabriela (Author) , Corso, Jasmin (Author) , Ströbel, Philipp (Author) , Wachter, Astrid (Author) , Beißbarth, Tim (Author) , Schnütgen, Frank (Author) , Cremer, Anjali (Author) , Haetscher, Nadine (Author) , Göllner, Stefanie (Author) , Rouhi, Arefeh (Author) , Palmqvist, Lars (Author) , Rieger, Michael A. (Author) , Schroeder, Timm (Author) , Bönig, Halvard (Author) , Müller-Tidow, Carsten (Author) , Kuchenbauer, Florian (Author) , Schütz, Ekkehard (Author) , Green, Anthony R. (Author) , Urlaub, Henning (Author) , Stegmaier, Kimberly (Author) , Humphries, R. Keith (Author) , Serve, Hubert (Author) , Oellerich, Thomas (Author)
Format: Article (Journal)
Language:English
Published: 20 April 2017
In: Cancer cell
Year: 2017, Volume: 31, Issue: 4, Pages: 549-562, e1-e11
ISSN:1878-3686
DOI:10.1016/j.ccell.2017.03.001
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.ccell.2017.03.001
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1535610817300636
Verlag, Volltext: https://www.sciencedirect.com/science/article/pii/S1535610817300636?via%3Dihub
Resolving-System, Volltext: https://dx.doi.org/10.1016/j.ccell.2017.03.001
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Author Notes:Sebastian Mohr, Carmen Doebele, Federico Comoglio, Tobias Berg, Julia Beck, Hanibal Bohnenberger, Gabriela Alexe, Jasmin Corso, Philipp Ströbel, Astrid Wachter, Tim Beissbarth, Frank Schnütgen, Anjali Cremer, Nadine Haetscher, Stefanie Göllner, Arefeh Rouhi, Lars Palmqvist, Michael A. Rieger, Timm Schroeder, Halvard Bönig, Carsten Müller-Tidow, Florian Kuchenbauer, Ekkehard Schütz, Anthony R. Green, Henning Urlaub, Kimberly Stegmaier, R. Keith Humphries, Hubert Serve, and Thomas Oellerich
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Summary: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. Hox genes; PU.1; Syk; leukemia; microRNA; signal transduction
Item Description:Erscheinungsdatum im PDF: April 10, 2017
Gesehen am 26.11.2024
Physical Description:Online Resource
ISSN:1878-3686
DOI:10.1016/j.ccell.2017.03.001

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