TY - JOUR
T1 - Molecular characterization stratifies VQ myeloma cells into two clusters with distinct risk signatures and drug responses
AU - Flietner, Evan
AU - Yu, Mei
AU - Poudel, Govinda
AU - Veltri, Anthony J.
AU - Zhou, Yun
AU - Rajagopalan, Adhithi
AU - Feng, Yubin
AU - Lasho, Terra
AU - Wen, Zhi
AU - Sun, Yuqian
AU - Patnaik, Mrinal M.
AU - Callander, Natalie S.
AU - Asimakopoulos, Fotis
AU - Wang, Demin
AU - Zhang, Jing
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/5/22
Y1 - 2023/5/22
N2 - Multiple myeloma (MM) is a cancer of malignant plasma cells in the bone marrow and extramedullary sites. We previously characterized a VQ model for human high-risk MM. The various VQ lines display different disease phenotypes and survival rates, suggesting significant intra-model variation. Here, we use whole-exome sequencing and copy number variation (CNV) analysis coupled with RNA-Seq to stratify the VQ lines into corresponding clusters: Group A cells had monosomy chromosome (chr) 5 and overexpressed genes and pathways associated with sensitivity to bortezomib (Btz) treatment in human MM patients. By contrast, Group B VQ cells carried recurrent amplification (Amp) of chr3 and displayed high-risk MM features, including downregulation of Fam46c, upregulation of cancer growth pathways associated with functional high-risk MM, and expression of Amp1q and high-risk UAMS-70 and EMC-92 gene signatures. Consistently, in sharp contrast to Group A VQ cells that showed short-term response to Btz, Group B VQ cells were de novo resistant to Btz in vivo. Our study highlights Group B VQ lines as highly representative of the human MM subset with ultrahigh risk.
AB - Multiple myeloma (MM) is a cancer of malignant plasma cells in the bone marrow and extramedullary sites. We previously characterized a VQ model for human high-risk MM. The various VQ lines display different disease phenotypes and survival rates, suggesting significant intra-model variation. Here, we use whole-exome sequencing and copy number variation (CNV) analysis coupled with RNA-Seq to stratify the VQ lines into corresponding clusters: Group A cells had monosomy chromosome (chr) 5 and overexpressed genes and pathways associated with sensitivity to bortezomib (Btz) treatment in human MM patients. By contrast, Group B VQ cells carried recurrent amplification (Amp) of chr3 and displayed high-risk MM features, including downregulation of Fam46c, upregulation of cancer growth pathways associated with functional high-risk MM, and expression of Amp1q and high-risk UAMS-70 and EMC-92 gene signatures. Consistently, in sharp contrast to Group A VQ cells that showed short-term response to Btz, Group B VQ cells were de novo resistant to Btz in vivo. Our study highlights Group B VQ lines as highly representative of the human MM subset with ultrahigh risk.
UR - http://www.scopus.com/inward/record.url?scp=85151924954&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85151924954&partnerID=8YFLogxK
U2 - 10.1038/s41388-023-02684-9
DO - 10.1038/s41388-023-02684-9
M3 - Article
C2 - 37031341
AN - SCOPUS:85151924954
SN - 0950-9232
VL - 42
SP - 1751
EP - 1762
JO - Oncogene
JF - Oncogene
IS - 21
ER -