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MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells

Jose L R Brito1, Brian Walker, Matthew Jenner

  • 1Institute for Cancer Research, Section of Haemato-Oncology, London, UK.

Haematologica
|December 9, 2008
PubMed
Abstract

Insights

The t(4;14) translocation in multiple myeloma up-regulates MMSET, impacting cell cycle and survival by altering gene expression. This study clarifies MMSET's role in t(4;14) myelomagenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The t(4;14) translocation is found in 15% of multiple myeloma cases, correlating with poor prognosis via an unclear mechanism.
  • This translocation up-regulates fibroblast growth factor receptor 3 (FGFR3) and the multiple myeloma SET domain (MMSET) genes.
  • The precise role of MMSET in t(4;14) multiple myeloma pathogenesis and its deregulated targets remain largely unknown.

Purpose of the Study:

  • To investigate the role of MMSET in t(4;14) multiple myeloma.
  • To identify genes and pathways affected by MMSET dysregulation in this cancer.
  • To elucidate the mechanism by which MMSET contributes to t(4;14) myelomagenesis.

Main Methods:

  • Analyzed MMSET expression using a novel antibody in multiple myeloma cell lines.
  • Utilized small interfering RNA (siRNA) mediated knockdown of MMSET to assess its role in myelomagenesis.
  • Performed expression microarrays to analyze differential gene expression following MMSET knockdown and in patient samples.

Main Results:

  • MMSET isoforms were exclusively up-regulated in t(4;14)-positive multiple myeloma cells.
  • MMSET suppression decreased cell viability and cell cycle progression in t(4;14) cells.
  • Reduced expression of cell cycle, apoptosis, and cell adhesion genes (e.g., CCND2, CASP1, ADAM9) was observed, with differential expression also noted in patient samples.

Conclusions:

  • MMSET dysregulation significantly impacts multiple myeloma cell proliferation and survival.
  • MMSET influences the expression of key genes involved in cell cycle regulation, cell adhesion, and apoptosis.
  • This study provides insights into the molecular mechanisms underlying t(4;14) multiple myeloma.

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