title: MAP3K8 kinase regulates myeloma growth by cell-autonomous and non-autonomous mechanisms involving myeloma-associated monocytes/macrophages.
abstract: Benefit from cytotoxic therapy in myeloma may be limited by the persistence of residual tumour cells within protective niches. We have previously shown that monocytes/macrophages acquire a proinflammatory transcriptional profile in the myeloma microenvironment. Here we report constitutive activation of MAP3K8 kinase-dependent pathways that regulate the magnitude and extent of inflammatory activity of monocytes/macrophages within myeloma niches. In myeloma tumour cells, MAP3K8 acts as mitogen-induced MAP3K in mitosis and is required for TNFα-mediated ERK activation. Pharmacological MAP3K8 inhibition results in dose-dependent, tumour cell-autonomous apoptosis despite contact with primary stroma. MAP3K8 blockade may disrupt crucial macrophage-tumour cell interactions within myeloma niches.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hebron
authors.forename: Chelsea
authors.initials: C
authors.lastname: Hope
authors.forename: Jaehyup
authors.initials: J
authors.lastname: Kim
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Jensen
authors.forename: Claire
authors.initials: C
authors.lastname: Flanagan
authors.forename: Neehar
authors.initials: N
authors.lastname: Bhatia
authors.forename: Ioanna
authors.initials: I
authors.lastname: Maroulakou
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Natalie
authors.initials: N
authors.lastname: Callander
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
authors.forename: Fotis
authors.initials: F
authors.lastname: Asimakopoulos
mesh_terms: D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology*; D009000:Monocytes / Q000201:enzymology* / Q000473:pathology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D018365:Neoplasm, Residual; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human