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Cancer Cell. 2017 Apr 10;31(4):549-562.e11. doi: 10.1016/j.ccell.2017.03.001.

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

Author information

1
Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
2
Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge CB2 0XY, UK.
3
Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; German Cancer Research Center and German Cancer Consortium, 69120 Heidelberg, Germany.
4
Chronix Biomedical, Goetheallee 8, 37073 Göttingen, Germany.
5
Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Straße 40, 37073 Göttingen, Germany.
6
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA.
7
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
8
Institute of Medical Statistics, University Medical Center Göttingen, Humboldtallee 32, 37073 Göttingen, Germany.
9
Department of Hematology and Oncology, University of Halle, Ernst-Grube-Street 40, 06120 Halle, Germany.
10
Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
11
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Su sahlgrenska, 41345 Gothenburg, Sweden.
12
Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, 4058 Basel, Switzerland.
13
Institute for Transfusion Medicine and Immunohematology, Goethe University, Sandhofstraße 1, 60590 Frankfurt, Germany.
14
Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany; Bioanalytics, Georg August University, Robert-Koch-Straße 40, 37073 Göttingen, Germany.
15
Terry Fox Laboratory, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada; Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
16
Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Cambridge Institute for Medical Research, Wellcome Trust/MRC Stem Cell Institute, Cambridge CB2 0XY, UK; German Cancer Research Center and German Cancer Consortium, 69120 Heidelberg, Germany. Electronic address: thomas.oellerich@kgu.de.

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.

KEYWORDS:

Hox genes; PU.1; Syk; leukemia; microRNA; signal transduction

PMID:
28399410
PMCID:
PMC5389883
DOI:
10.1016/j.ccell.2017.03.001
[Indexed for MEDLINE]
Free PMC Article

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