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Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia.

Journal article
Authors 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
Thomas Oellerich
Published in Cancer cell
Volume 31
Issue 4
Pages 549-562.e11
ISSN 1878-3686
Publication year 2017
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Pages 549-562.e11
Language en
Links dx.doi.org/10.1016/j.ccell.2017.03....
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Molecular medicine (genetics and pathology)

Abstract

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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