MMSET is highly expressed and associated with aggressiveness in neuroblastoma

Heidi Rye Hudlebusch, Julie Skotte, Eric Santoni-Rugiu, Zarah Glad Zimling, Michael James Lees, Ronald Simon, Guido Sauter, Rossella Rota, Maria Antonietta De Ioris, Micaela Quarto, Jens Vilstrup Johansen, Mette Jørgensen, Catherine Rechnitzer, Lisa Leth Maroun, Henrik Schrøder, Bodil Laub Petersen, Kristian Helin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4226-4235
Number of pages10
JournalCancer Research
Volume71
Issue number12
DOIs
Publication statusPublished - Jun 15 2011

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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