English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation.

Oellerich, T., Mohr, S., Corso, J., Beck, J., Döbele, C., Braun, H., et al. (2015). FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation. Blood, 125(12), 1936-1947. doi:10.1182/blood-2014-06-585216.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-128A-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-1113-E
Genre: Journal Article

Files

show Files
hide Files
:
2156713.pdf (Publisher version), 4MB
 
File Permalink:
-
Name:
2156713.pdf
Description:
-
Visibility:
Restricted (Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute), Göttingen; )
MIME-Type / Checksum:
application/pdf
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Locators

show
hide
Description:
-

Creators

show
hide
 Creators:
Oellerich, T., Author
Mohr, S., Author
Corso, J.1, Author              
Beck, J., Author
Döbele, C., Author
Braun, H., Author
Cremer, A., Author
Münch, S., Author
Wicht, J., Author
Oellerich, M. F., Author
Bug, G., Author
Bohnenberger, H., Author
Perske, C., Author
Schütz, E., Author
Urlaub, H.1, Author              
Serve, H., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

Content

show
hide
Free keywords: -
 Abstract: Acute myeloid leukemia (AML) is driven by niche-derived and cell-autonomous stimuli. Although many cell-autonomous disease drivers are known, niche-dependent signaling in the context of the genetic disease heterogeneity has been difficult to investigate. Here, we analyzed the role of Bruton tyrosine kinase (BTK) in AML. BTK was frequently expressed, and its inhibition strongly impaired the proliferation and survival of AML cells also in the presence of bone marrow stroma. By interactome analysis, (phospho)proteomics, and transcriptome sequencing, we characterized BTK signaling networks. We show that BTK-dependent signaling is highly context dependent. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)–positive AML, BTK mediates FLT3-ITD–dependent Myc and STAT5 activation, and combined targeting of FLT3-ITD and BTK showed additive effects. In Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)–negative AML, BTK couples Toll-like receptor 9 (TLR9) activation to nuclear factor κΒ and STAT5. Both BTK-dependent transcriptional programs were relevant for cell cycle progression and apoptosis regulation. Thus, we identify context-dependent oncogenic driver events that may guide subtype-specific treatment strategies and, for the first time, point to a role of TLR9 in AML. Clinical evaluation of BTK inhibitors in AML seems warranted.

Details

show
hide
Language(s): eng - English
 Dates: 2015-03-19
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1182/blood-2014-06-585216
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Blood
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 125 (12) Sequence Number: - Start / End Page: 1936 - 1947 Identifier: -