title: A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression.
abstract: Modulating aberrant transcription of oncogenes is a relatively unexplored opportunity in cancer therapeutics. In approximately 10% of multiple myelomas, the initiating oncogenic event is translocation of musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a transcriptional activator of key target genes, including cyclinD2. Our prior work showed that MAF is up-regulated in an additional 30% of multiple myeloma cases. The present study describes a common mechanism inducing MAF transcription in both instances. The second mode of MAF transcription occurred in myelomas with multiple myeloma SET domain (MMSET) translocation. MMSET knockdown decreased MAF transcription and cell viability. A small-molecule screen found an inhibitor of mitogen-activated protein kinase kinase (MEK), which activates extracellular signal-regulated kinase (ERK)-MAP kinases, reduced MAF mRNA in cells representing MMSET or MAF subgroups. ERK activates transcription of FOS, part of the AP-1 transcription factor. By chromatin immunoprecipitation, FOS bound the MAF promoter, and MEK inhibition decreased this interaction. MEK inhibition selectively induced apoptosis in MAF-expressing myelomas, and FOS inactivation was similarly toxic. Reexpression of MAF rescued cells from death induced by MMSET depletion, MEK inhibition, or FOS inactivation. The data presented herein demonstrate that the MEK-ERK pathway regulates MAF transcription, providing molecular rationale for clinical evaluation of MEK inhibitors in MAF-expressing myeloma.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, 10 Center Dr., Bethesda, MD 20892-1374, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
authors.forename: Lidia
authors.initials: L
authors.lastname: Hernandez
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Adriana
authors.initials: A
authors.lastname: Zingone
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamy
authors.forename: Lloyd T
authors.initials: LT
authors.lastname: Lam
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Hurt
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.forename: W Michael
authors.initials: WM
authors.lastname: Kuehl
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D017209:Apoptosis; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009101:Multiple Myeloma / Q000188:drug therapy*; D051256:Oncogene Protein v-maf / Q000235:genetics*; D011494:Protein Kinases / Q000627:therapeutic use*; D012097:Repressor Proteins / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D051256:Oncogene Protein v-maf; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; D011494:Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases