Shen YJ, Mishima Y, Shi J, Sklavenitis-Pistofidis R, Redd RA, Moschetta M, Manier S, Roccaro AM, Sacco A, Tai YT, Mercier F, Kawano Y, Su NK, Berrios B, Doench JG, Root DE, Michor F, Scadden DT, Ghobrial IM. 2021. Progression signature underlies clonal evolution and dissemination of multiple myeloma. Blood. 137(17):2360-2372. Pubmed: 33150374 DOI:10.1182/blood.2020005885


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 in MM progression 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.
© 2021 by The American Society of Hematology.

Related Faculty

Photo of David Scadden

David Scadden’s laboratory is dedicated to discovering the principles governing blood cell production, with the ultimate goal of guiding the development of therapies for blood disorders and cancer.

Photo of Franziska Michor

Franziska Michor uses the tools of theoretical evolutionary biology, applied mathematics, statistics, and computational biology to address important questions in cancer research.

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