Progression signature underlies clonal evolution and dissemination of multiple myeloma

Abstract

Clonal evolution drives tumor progression, dissemination and relapse in multiple myeloma (MM), with most patients dying of relapsed disease. This multi-stage 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 datasets. 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 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.

Deciphering spatial genomic heterogeneity at a single cell resolution in multiple myeloma

“…The anti-metastatic tumor suppressor gene AZGP1 was also downregulated in the EMD from patient RRMM01, while a small subset of PC with lower expression levels of AZGP1 could also be identi ed in BM. Our ndings and recent preclinical studies (27) support the hypothesis that OL are derived from a common PC ancestor developing molecular features to cause myeloma bone disease. Thus, MM would behave like a solid tumor with PC metastasizing to distant locations, inducing OL.…”

“…The respective genes have been connected to the extramedullary spread of MM in the past (25). JUN/FOS have been associated with malignant B-cell transformation (26) and progression of MM in a recent preclinical study (27). GSEA con rmed that downregulation of genes connected to regular B-cell function were a common feature of PC from OL.…”

“…Downregulation of JUN/FOS, DUSP1 and HBB has been connected to extramedullary spread of MM in the past (25). Furthermore, JUN/FOS are linked to the malignant transformation of Bcells (26) and dissemination of clonal PC in a preclinical model (27). GSEA con rmed that downregulation of genes in pathways associated with normal B-cell was common in PC from the OL (Figure 3F).…”

Clonal Evolution of Multiple Myeloma—Clinical and Diagnostic Implications

“…The role of the bone marrow microenvironment in the survival and proliferation of plasma cells and the development of treatment resistance in MM is well-established [ 66 ]. Tumor microenvironment is a complex heterogeneous structure [ 56 , 81 , 82 ] providing selection forces that enforce continuous competition between the subclones. Shen et al, using an animal model of MM to study clonal behavior within the bone marrow microenvironment, showed that distant bone marrow sites can only be colonized by a few clones well-adapted to the local microenvironment [ 82 ], again demonstrating that autonomous factors of plasma cells are not sufficient to independently drive MM progression.…”

The Impact of Induction Regimes on Immune Responses in Patients with Multiple Myeloma

“…Multiple myeloma (MM) is a malignancy of plasma cells and the second most common hematological cancer. MM results from an antigen-experienced B cell clone that undergoes transformation, clonal evolution and expansion, and eventual proliferation in the bone marrow (BW) [1]. This process is mirrored by laboratory-defined, pre-malignant states known as monoclonal gammopathy of undefined significance (MGUS) and smoldering MM (SMM), which are eventually replaced by a state of active, clinical disease.…”