MMSET is highly expressed and associated with aggressiveness in neuroblastoma

Heidi Rye Hudlebusch; Julie Skotte; Eric Santoni-Rugiu; Zarah Glad Zimling; Michael J Lees; Ronald Simon; Guido Sauter; Rossella Rota; Maria Antonietta De Ioris; Micaela Quarto; Jens V Johansen; Mette Jorgensen; Catherine Rechnitzer; Lisa L Maroun; Henrik Schrøder; Bodil L Petersen; Kristian Helin; 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

doi:10.1158/0008-5472.can-10-3810

MMSET is highly expressed and associated with aggressiveness in neuroblastoma

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

46 Citations (Scopus)

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 language	English
Journal	Cancer Research
Volume	71
Issue number	12
Pages (from-to)	4226-35
Number of pages	10
ISSN	0008-5472
DOIs	https://doi.org/10.1158/0008-5472.can-10-3810
Publication status	Published - 15 Jun 2011

Keywords

Cell Differentiation
Cell Proliferation
Genes, myc
Histone-Lysine N-Methyltransferase
Humans
Neural Stem Cells
Neuroblastoma
Prognosis
Repressor Proteins

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Hudlebusch, H. R., Skotte, J., Santoni-Rugiu, E., Zimling, Z. G., Lees, M. J., Simon, R., Sauter, G., Rota, R., De Ioris, M. A., Quarto, M., Johansen, J. V., Jorgensen, M., Rechnitzer, C., Maroun, L. L., Schrøder, H., Petersen, B. L., Helin, K., Hudlebusch, H. R., Skotte, J., ... Helin, K. (2011). MMSET is highly expressed and associated with aggressiveness in neuroblastoma. Cancer Research, 71(12), 4226-35. https://doi.org/10.1158/0008-5472.can-10-3810

Hudlebusch, HR, Skotte, J, Santoni-Rugiu, E, Zimling, ZG, Lees, MJ, Simon, R, Sauter, G, Rota, R, De Ioris, MA, Quarto, M, Johansen, JV, Jorgensen, M, Rechnitzer, C, Maroun, LL, Schrøder, H, Petersen, BL, Helin, K, Hudlebusch, HR, Skotte, J, Santoni-Rugiu, E, Zimling, ZG, Lees, MJ, Simon, R, Sauter, G, Rota, R, De Ioris, MA, Quarto, M, Johansen, JV, Jørgensen, M, Rechnitzer, C, Maroun, LL, Schrøder, H, Petersen, BL & Helin, K 2011, 'MMSET is highly expressed and associated with aggressiveness in neuroblastoma', Cancer Research, vol. 71, no. 12, pp. 4226-35. https://doi.org/10.1158/0008-5472.can-10-3810

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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.",

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T1 - MMSET is highly expressed and associated with aggressiveness in neuroblastoma

AU - Hudlebusch, Heidi Rye

AU - Skotte, Julie

AU - Santoni-Rugiu, Eric

AU - Zimling, Zarah Glad

AU - Lees, Michael J

AU - Simon, Ronald

AU - Sauter, Guido

AU - Rota, Rossella

AU - De Ioris, Maria Antonietta

AU - Quarto, Micaela

AU - Johansen, Jens V

AU - Jorgensen, Mette

AU - Rechnitzer, Catherine

AU - Maroun, Lisa L

AU - Schrøder, Henrik

AU - Petersen, Bodil L

AU - Helin, Kristian

AU - Hudlebusch, Heidi Rye

AU - Skotte, Julie

AU - Santoni-Rugiu, Eric

AU - Zimling, Zarah Glad

AU - Lees, Michael James

AU - Simon, Ronald

AU - Sauter, Guido

AU - Rota, Rossella

AU - De Ioris, Maria Antonietta

AU - Quarto, Micaela

AU - Johansen, Jens Vilstrup

AU - Jørgensen, Mette

AU - Rechnitzer, Catherine

AU - Maroun, Lisa Leth

AU - Schrøder, Henrik

AU - Petersen, Bodil Laub

AU - Helin, Kristian

PY - 2011/6/15

Y1 - 2011/6/15

N2 - 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.

AB - 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.

KW - Cell Differentiation

KW - Cell Proliferation

KW - Genes, myc

KW - Histone-Lysine N-Methyltransferase

KW - Humans

KW - Neural Stem Cells

KW - Neuroblastoma

KW - Prognosis

KW - Repressor Proteins

U2 - 10.1158/0008-5472.can-10-3810

DO - 10.1158/0008-5472.can-10-3810

M3 - Journal article

C2 - 21527557

SN - 0008-5472

VL - 71

SP - 4226

EP - 4235

JO - Cancer Research

JF - Cancer Research

IS - 12

ER -

MMSET is highly expressed and associated with aggressiveness in neuroblastoma

Abstract

Keywords

UN SDGs

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