Progression signature underlies clonal evolution and dissemination of multiple myeloma

Clonal evolution drives tumor progression, dissemination, and relapse in multiple myeloma (MM), with most patients dying of relapsed disease. This multistage process requires tumor cells to enter the circulation, extravasate, and colonize distant bone marrow (BM) sites. Here, we developed a fluorescent or DNA-barcode clone-tracking system on MM PrEDiCT (progression through evolution and dissemination of clonal tumor cells) xenograft mouse model to study clonal behavior within the BM microenvironment. We showed that only the few clones that successfully adapt to the BM microenvironment can enter the circulation and colonize distant BM sites. RNA sequencing of primary and distant-site MM tumor cells revealed a progression signature sequentially activated along human MM progression and significantly associated with overall survival when evaluated against patient data sets. A total of 28 genes were then computationally predicted to be master regulators (MRs) of MM progression. HMGA1 and PA2G4 were validated in vivo using CRISPR-Cas9 in the PrEDiCT model and were shown to be significantly depleted in distant BM sites, indicating their role inMMprogression and dissemination. Loss of HMGA1 and PA2G4 also compromised the proliferation, migration, and adhesion abilities of MM cells in vitro. Overall, our model successfully recapitulates key characteristics of human MM disease progression and identified potential new therapeutic targets for MM.

Automated summary

Clonal evolution plays a key role in tumor progression, dissemination, and relapse in multiple myeloma (MM). By developing a clone-tracking system, researchers studied clonal behavior in the bone marrow microenvironment, identifying specific clones able to adapt and colonize distant sites. RNA sequencing revealed a progression signature in MM tumor cells, leading to the prediction of 28 master regulators, with HMGA1 and PA2G4 validated as key players in MM progression and dissemination, impacting cell functions like proliferation, migration, and adhesion. This study successfully replicates key characteristics of human MM disease progression and suggests potential therapeutic targets.