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MAP 3K8 kinase regulates myeloma growth by cell‐autonomous and non‐autonomous mechanisms involving myeloma‐associated monocytes/macrophages
Author(s) -
Hebron Ellen,
Hope Chelsea,
Kim Jaehyup,
Jensen Jeffrey L.,
Flanagan Claire,
Bhatia Neehar,
Maroulakou Ioanna,
Mitsiades Constantine,
Miyamoto Shigeki,
Callander Natalie,
Hematti Peiman,
Asimakopoulos Fotis
Publication year - 2013
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12175
Subject(s) - stromal cell , multiple myeloma , cancer research , biology , mapk/erk pathway , macrophage , proinflammatory cytokine , mitogen activated protein kinase , microbiology and biotechnology , kinase , immunology , inflammation , in vitro , biochemistry
Summary 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 MAP 3K8 kinase‐dependent pathways that regulate the magnitude and extent of inflammatory activity of monocytes/macrophages within myeloma niches. In myeloma tumour cells, MAP 3K8 acts as mitogen‐induced MAP 3K in mitosis and is required for TNF α‐mediated ERK activation. Pharmacological MAP 3K8 inhibition results in dose‐dependent, tumour cell‐autonomous apoptosis despite contact with primary stroma. MAP 3K8 blockade may disrupt crucial macrophage‐tumour cell interactions within myeloma niches.