Progression signature underlies clonal evolution and dissemination of multiple myeloma.
Adaptor Proteins, Signal Transducing
/ antagonists & inhibitors
Animals
Apoptosis
Biomarkers, Tumor
/ genetics
Bone Marrow
/ metabolism
CRISPR-Cas Systems
Cell Adhesion
Cell Movement
Cell Proliferation
Clonal Evolution
Disease Models, Animal
Disease Progression
Female
Gene Expression Regulation, Neoplastic
HMGA1a Protein
/ antagonists & inhibitors
Humans
Mice
Mice, SCID
Multiple Myeloma
/ genetics
Neoplasm Recurrence, Local
/ genetics
Prognosis
RNA-Binding Proteins
/ antagonists & inhibitors
Survival Rate
Tumor Cells, Cultured
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
29 04 2021
29 04 2021
Historique:
received:
25
03
2020
accepted:
07
10
2020
pubmed:
6
11
2020
medline:
15
12
2021
entrez:
5
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33150374
pii: S0006-4971(21)00918-6
doi: 10.1182/blood.2020005885
pmc: PMC8085483
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Biomarkers, Tumor
0
HMGA1 protein, human
0
PA2G4 protein, human
0
RNA-Binding Proteins
0
HMGA1a Protein
124544-67-8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2360-2372Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 by The American Society of Hematology.
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