Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma

Area of Science:

• Hematology
• Genetics
• Pharmacology

Background:

• Multiple myeloma (MM) outcomes have improved with new therapies, but drug resistance and relapse remain significant challenges.
• Understanding the genetic basis of relapse and drug resistance is crucial for improving MM treatment.
• Previous studies have identified genetic mutations in relapsed/resistant MM, but their direct causal link to drug sensitivity is not fully understood.

Purpose of the Study:

• To systematically evaluate the functional impact of relapse-specific gene mutations on drug sensitivity in multiple myeloma.
• To identify specific genetic alterations that confer resistance or sensitivity to key MM drugs.

Main Methods:

• Combined whole-exome sequencing (WES) of longitudinal patient samples from 16 MM patients.
• CRISPR-Cas9 drug resistance screens were performed for lenalidomide, bortezomib, dexamethasone, and melphalan.
• Functional validation of 170 relapse-specific mutations identified through WES.

Main Results:

• WES identified numerous newly acquired mutations in MM patients, including recurrent mutations in TP53, DNAH5, and WSCD2.
• CRISPR screens functionally linked 15 mutations to drug resistance, identifying specific genes associated with resistance to lenalidomide, dexamethasone, bortezomib, and melphalan.
• Inactivation of DNA damage repair genes enhanced sensitivity to chemotherapy, while resistance patterns were drug-specific and correlated with clonal evolution.

Conclusions:

• Specific genetic alterations functionally impact drug sensitivity and resistance in multiple myeloma.
• The findings highlight the drug-specific nature of resistance mechanisms and clonal evolution in MM.
• Establishing these functional associations will aid in the future personalization of multiple myeloma treatment strategies.