title: MMSET is highly expressed and associated with aggressiveness in neuroblastoma.
abstract: MMSET (WHSC1/NSD2) is a SET domain-containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n = 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and postchemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acid-induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis.
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Denmark.
authors.forename: Heidi Rye
authors.initials: HR
authors.lastname: Hudlebusch
authors.forename: Julie
authors.initials: J
authors.lastname: Skotte
authors.forename: Eric
authors.initials: E
authors.lastname: Santoni-Rugiu
authors.forename: Zarah Glad
authors.initials: ZG
authors.lastname: Zimling
authors.forename: Michael James
authors.initials: MJ
authors.lastname: Lees
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Rossella
authors.initials: R
authors.lastname: Rota
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: De Ioris
authors.forename: Micaela
authors.initials: M
authors.lastname: Quarto
authors.forename: Jens Vilstrup
authors.initials: JV
authors.lastname: Johansen
authors.forename: Mette
authors.initials: M
authors.lastname: Jørgensen
authors.forename: Catherine
authors.initials: C
authors.lastname: Rechnitzer
authors.forename: Lisa Leth
authors.initials: LL
authors.lastname: Maroun
authors.forename: Henrik
authors.initials: H
authors.lastname: Schrøder
authors.forename: Bodil Laub
authors.initials: BL
authors.lastname: Petersen
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D016259:Genes, myc; D011495:Histone-Lysine N-Methyltransferase / Q000032:analysis / Q000502:physiology*; D006801:Humans; D058953:Neural Stem Cells / Q000737:chemistry / Q000166:cytology; D009447:Neuroblastoma / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D011379:Prognosis; D012097:Repressor Proteins / Q000032:analysis / Q000502:physiology*
chemical_list: D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human