title: FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation.
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.
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany; German Cancer Consortium, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mohr
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany;
authors.forename: Jasmin
authors.initials: J
authors.lastname: Corso
authors.affiliation: Chronix Biomedical, San Jose, CA;
authors.forename: Julia
authors.initials: J
authors.lastname: Beck
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany;
authors.forename: Carmen
authors.initials: C
authors.lastname: Döbele
authors.affiliation: German Cancer Consortium, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany;
authors.forename: Helene
authors.initials: H
authors.lastname: Braun
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany;
authors.forename: Anjali
authors.initials: A
authors.lastname: Cremer
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany;
authors.forename: Silvia
authors.initials: S
authors.lastname: Münch
authors.affiliation: German Cancer Consortium, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany;
authors.forename: Johannes
authors.initials: J
authors.lastname: Wicht
authors.affiliation: Department of Medicine III, Cardiology, Goethe University, Frankfurt, Germany; and.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Oellerich
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany;
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.affiliation: Department of Pathology and.
authors.forename: Hanibal
authors.initials: H
authors.lastname: Bohnenberger
authors.affiliation: Department of Pathology and.
authors.forename: Christina
authors.initials: C
authors.lastname: Perske
authors.affiliation: Chronix Biomedical, San Jose, CA;
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Schütz
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany; Bioanalytics, Georg August University, Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany; German Cancer Consortium, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany;
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
mesh_terms: D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004789:Enzyme Activation; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007150:Immunohistochemistry; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000378:metabolism; D013058:Mass Spectrometry; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D025521:Tumor Suppressor Proteins; D014443:Tyrosine; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human