Identification of a CD138-Negative Therapy-Resistant Subpopulation in Multiple Myeloma with Vulnerability to Splicing...

Area of Science:

• Hematology
• Molecular Biology
• Genetics

Background:

• Therapy resistance in multiple myeloma (MM) is a significant clinical challenge.
• The underlying molecular mechanisms driving MM therapy resistance are not fully understood.

Purpose of the Study:

• To investigate the cellular heterogeneity and molecular basis of therapy resistance in multiple myeloma.
• To identify novel therapeutic targets for overcoming MM treatment resistance.

Main Methods:

• Single-cell RNA sequencing and VDJ-targeted sequencing of primary MM cells.
• CRISPR/Cas9 screening to identify vulnerabilities in resistant subpopulations.
• Genetic and pharmacological inhibition of RNA-binding protein 39 (RBM39).

Main Results:

• Identified distinct therapy-resistant MM subpopulations within the CD138- fraction.
• Discovered increased differential splicing and overexpression of SR protein family splicing factors, including RBM39, in resistant cells.
• Demonstrated selective lethality of RBM39 inhibition in therapy-resistant CD138- MM cells.

Conclusions:

• The splicing pathway, particularly targeting RBM39, represents a promising therapeutic strategy for overcoming multiple myeloma resistance.
• Understanding cellular heterogeneity is crucial for developing effective MM treatments.