A niche-dependent myeloid transcriptome signature defines dormant myeloma cells

Area of Science:

• Hematology
• Molecular Biology
• Oncology

Background:

• Targeted therapies have improved multiple myeloma outcomes, but disease relapse due to drug-resistant dormant cells remains a challenge.
• Dormant myeloma cells in bone marrow niches are difficult to study but are implicated in relapse.
• Understanding the molecular basis of myeloma cell dormancy is crucial for developing effective treatments.

Purpose of the Study:

• To develop a method for analyzing the transcriptome of individual dormant myeloma cells.
• To identify molecular signatures associated with dormant myeloma cells.
• To explore therapeutic strategies targeting dormant myeloma cells.

Main Methods:

• Single-cell transcriptome sequencing of dormant myeloma cells from mouse bone marrow.
• Coculture of myeloma cells with osteoblastic cells to study niche interactions.
• Pharmacological inhibition of AXL (a key gene identified in dormant cells).
• Analysis of gene expression in human multiple myeloma and precursor disease cohorts.

Main Results:

• Dormant myeloma cells exhibit a distinct transcriptome signature enriched for immune and myeloid differentiation genes.
• Coculture with osteoblastic cells induced this myeloid gene signature.
• Inhibition of AXL released dormant cells and promoted proliferation.
• The myeloid dormancy signature was inversely correlated with multiple myeloma in human cohorts but associated with improved survival in patients, suggesting it marks disease progression.

Conclusions:

• The osteoblastic niche induces a myeloid gene signature in myeloma cells, which is associated with disease progression and survival.
• AXL is a potential therapeutic target to overcome dormancy and eradicate residual myeloma cells.
• The identified dormancy signature may serve as a prognostic marker and a target for novel therapies in multiple myeloma.