c-FOS Confers Stem Cell-like Features to Multiple Myeloma Cells in a Bone Marrow Microenvironment

Area of Science:

• Hematologic Malignancies
• Cancer Biology
• Drug Resistance Mechanisms

Background:

• Multiple myeloma (MM) is a significant hematologic malignancy with a poor prognosis.
• Despite advances with novel agents, MM remains incurable due to high relapse rates.
• The bone marrow microenvironment (BMME) contributes to drug resistance and minimal residual disease (MRD), fueling relapse.

Purpose of the Study:

• To investigate the role of the AP-1 transcription factor c-FOS in MM drug resistance and cancer stem cell-like properties within the BMME.
• To explore the therapeutic potential of inhibiting c-FOS in MM.

Main Methods:

• In vitro and in vivo studies using MM cells and a murine serial transplantation model.
• Analysis of c-FOS and IRF4 expression.
• Assessment of drug resistance and cancer stem cell-like features.
• Evaluation of the effect of the c-FOS inhibitor T-5224.

Main Results:

• Upregulated c-FOS expression correlates with poor prognosis and confers cancer stem cell-like features, including drug resistance, in MM cells within the BMME.
• c-FOS upregulates IRF4 expression, contributing to these phenotypes.
• Inhibition of c-FOS by T-5224 prevented MM cell regeneration in a serial transplantation assay by downregulating IRF4.

Conclusions:

• c-FOS plays a functional role in conferring cancer stem cell-like features to MM cells within the BMME.
• c-FOS inhibition represents a promising therapeutic strategy to eliminate drug-resistant, cancer stem cell-like MM cells in MRD and improve patient outcomes.