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High-level expression of Mastermind-like 2 contributes to aberrant activation of the NOTCH signaling pathway in human

K Köchert1, K Ullrich, S Kreher

  • 1Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.

Oncogene
|December 2, 2010
PubMed

Insights

Aberrant Mastermind-like (MAML) protein expression activates NOTCH signaling in lymphoma. Inhibiting MAML reduces lymphoma cell proliferation, suggesting MAML and the NOTCH transcriptional complex as potential therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • NOTCH signaling pathway dysregulation is implicated in various human cancers.
  • Activating mutations are a known mechanism for NOTCH pathway hyperactivation.
  • Alternative mechanisms for NOTCH pathway activation in malignancies require investigation.

Purpose of the Study:

  • To investigate the role of Mastermind-like (MAML) proteins in NOTCH pathway activation in human lymphoma.
  • To explore MAML2 as a potential therapeutic target in classical Hodgkin lymphoma (cHL).

Main Methods:

  • Quantitative analysis of MAML2 expression in lymphoma cells versus normal B cells.
  • Inhibition of MAML protein activity using dominant-negative constructs and small hairpin RNAs (shRNAs).
  • Assessment of NOTCH target gene expression (HES7, HEY1) and cell proliferation.
  • Analysis of NOTCH gene-expression signatures and in vitro disruption of the NOTCH transcriptional complex (NTC).

Main Results:

  • High-level MAML2 expression was observed in B cell lymphomas, including cHL, compared to normal B cells.
  • Inhibition of MAML activity downregulated NOTCH target genes and reduced cHL cell proliferation.
  • NOTCH gene-expression signatures confirmed cell-autonomous NOTCH activity in cHL.
  • MAML-derived peptides disrupted NTC formation and blocked NOTCH activity in vitro.

Conclusions:

  • Aberrant MAML expression is an alternative mechanism for NOTCH pathway activation in lymphoma.
  • Targeting MAML proteins and the NTC presents a potential therapeutic strategy for NOTCH-dependent malignancies.

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