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A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression

Christina M Annunziata1, Lidia Hernandez, R Eric Davis

  • 1Metabolism Branch, Center for Cancer Research, National Cancer Institute, 10 Center Dr., Bethesda, MD 20892-1374, USA.

Blood
|December 18, 2010
PubMed

Insights

Aberrant transcription of the musculoaponeurotic fibrosarcoma oncogene homolog (MAF) drives multiple myeloma. Targeting the MEK-ERK pathway offers a novel therapeutic strategy by inhibiting MAF transcription and inducing cancer cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Aberrant oncogene transcription is a therapeutic target in cancer.
  • Musculoaponeurotic fibrosarcoma oncogene homolog (MAF) is a key transcriptional activator implicated in multiple myeloma (MM).
  • MAF is translocated in 10% of MM cases and upregulated in an additional 30%.

Purpose of the Study:

  • To elucidate a common mechanism driving MAF transcription in multiple myeloma.
  • To investigate the role of the MEK-ERK pathway in regulating MAF.
  • To evaluate MEK inhibitors as a therapeutic strategy for MAF-expressing MM.

Main Methods:

  • Investigated MAF transcription in MMSET-translocated and MAF-translocated MM cell lines.
  • Utilized small-molecule screening to identify MEK inhibitors.
  • Performed chromatin immunoprecipitation to assess FOS binding to the MAF promoter.
  • Assessed the impact of MEK inhibition and FOS inactivation on cell viability and apoptosis.

Main Results:

  • MMSET knockdown reduced MAF transcription and MM cell viability.
  • MEK inhibitors decreased MAF mRNA levels in relevant MM subgroups.
  • FOS, activated by ERK, binds the MAF promoter; MEK inhibition disrupted this interaction.
  • MEK inhibition and FOS inactivation selectively induced apoptosis in MAF-expressing MM cells.

Conclusions:

  • The MEK-ERK pathway is a key regulator of MAF transcription in multiple myeloma.
  • Targeting MEK offers a promising therapeutic avenue for MAF-driven multiple myeloma.
  • Re-expression of MAF rescued cells from MMSET depletion, MEK inhibition, and FOS inactivation, confirming MAF's central role.

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