TY  - JOUR
A1  - Mohr, Sebastian
A1  - Döbele, Carmen
A1  - Comoglio, Federico
A1  - Berg, Tobias
A1  - Beck, Julia
A1  - Bohnenberger, Hanibal
A1  - Alexe, Gabriela
A1  - Corso, Jasmin
A1  - Ströbel, Philipp
A1  - Wachter, Astrid
A1  - Beißbarth, Tim
A1  - Schnütgen, Frank
A1  - Cremer, Anjali
A1  - Hätscher, Nadine
A1  - Göllner, Stefanie
A1  - Rouhi, Arefeh
A1  - Palmqvist, Lars
A1  - Rieger, Michael A.
A1  - Schroeder, Timm
A1  - Bönig, Halvard-Björn
A1  - Müller-Tidow, Carsten
A1  - Kuchenbauer, Florian
A1  - Schütz, Ekkehard
A1  - Green, Anthony R.
A1  - Urlaub, Henning
A1  - Stegmaier, Kimberly
A1  - Humphries, R. Keith
A1  - Serve, Hubert
A1  - Oellerich, Thomas
T1  - Hoxa9 and Meis1 cooperatively induce addiction to syk signaling by suppressing miR-146a in acute myeloid leukemia
T2  - Cancer cell
N2  - 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.
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/43728
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-437282
SN  - 1878-3686
SN  - 1535-6108
N1  - © 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/).
VL  - 31
IS  - 4, e11
SP  - 549
EP  - 562
PB  - Cell Press ; Elsevier
CY  - Cambridge, Mass. ; New York, NY
ER  -