title: The TAK1-NF-κB axis as therapeutic target for AML.
abstract: Development and maintenance of leukemia can be partially attributed to alterations in (anti)-apoptotic gene expression. Genome-wide transcriptome analyses revealed that 89 apoptosis-associated genes were differentially expressed between patient acute myeloid leukemia (AML) CD34(+) cells and normal bone marrow (NBM) CD34(+) cells. Among these, transforming growth factor-β activated kinase 1 (TAK1) was strongly upregulated in AML CD34(+) cells. Genetic downmodulation or pharmacologic inhibition of TAK1 activity strongly impaired primary AML cell survival and cobblestone formation in stromal cocultures. TAK1 inhibition was mainly due to blockade of the nuclear factor κB (NF-κB) pathway, as TAK1 inhibition resulted in reduced levels of P-IκBα and p65 activity. Overexpression of a constitutive active variant of NF-κB partially rescued TAK1-depleted cells from apoptosis. Importantly, NBM CD34(+) cells were less sensitive to TAK1 inhibition compared with AML CD34(+) cells. Knockdown of TAK1 also severely impaired leukemia development in vivo and prolonged overall survival in a humanized xenograft mouse model. In conclusion, our results indicate that TAK1 is frequently overexpressed in AML CD34(+) cells, and that TAK1 inhibition efficiently targets leukemic stem/progenitor cells in an NF-κB-dependent manner.
authors.affiliation: Department of Experimental Hematology, University Medical Center Groningen, and Department of Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Matthieu Cornelis Johannes
authors.initials: MC
authors.lastname: Bosman
authors.affiliation: Department of Experimental Hematology, University Medical Center Groningen, and.
authors.forename: Hein
authors.initials: H
authors.lastname: Schepers
authors.affiliation: Department of Experimental Hematology, University Medical Center Groningen, and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jaques
authors.affiliation: Department of Experimental Hematology, University Medical Center Groningen, and.
authors.forename: Annet Zwaantien
authors.initials: AZ
authors.lastname: Brouwers-Vos
authors.affiliation: Department of Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Wim Johannes
authors.initials: WJ
authors.lastname: Quax
authors.affiliation: Department of Experimental Hematology, University Medical Center Groningen, and.
authors.forename: Jan Jacob
authors.initials: JJ
authors.lastname: Schuringa
authors.affiliation: Department of Experimental Hematology, University Medical Center Groningen, and.
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects*; D059467:Transcriptome; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D063268:Sialic Acid Binding Ig-like Lectin 3; D000099151:MAP Kinase Kinase Kinase 7