Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma

Minjie Gao; Hua Bai; Yogesh Jethava; Yujie Wu; Yuqi Zhu; Ye Yang; Jiliang Xia; Huojun Cao; Reinaldo Franqui-Machin; Kalyan Nadiminti; Gregory S Thomas; Mohamed E Salama; Peter Altevogt; Gail Bishop; Michael Tomasson; Siegfried Janz; Jumei Shi; Lijuan Chen; Ivana Frech; Guido Tricot; Fenghuang Zhan

doi:10.1093/jnci/djz159

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Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma

Journal article

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Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma

Minjie Gao, Hua Bai, Yogesh Jethava, Yujie Wu, Yuqi Zhu, Ye Yang, Jiliang Xia, Huojun Cao, Reinaldo Franqui-Machin, Kalyan Nadiminti, …

JNCI : Journal of the National Cancer Institute, Vol.112(5), pp.507-515

05/01/2020

DOI: 10.1093/jnci/djz159

PMCID: PMC7225664

PMID: 31406992

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Abstract

Abstract Background Treatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant. Methods Gene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group. Results CD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo. Conclusion Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.

Details

Title: Subtitle: Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma
Creators: Minjie Gao - University of Iowa
Hua Bai - University of Iowa
Yogesh Jethava - University of Iowa
Yujie Wu - Nanjing Medical University
Yuqi Zhu - University of Iowa
Ye Yang - University of Iowa
Jiliang Xia - University of Iowa
Huojun Cao - University of Iowa
Reinaldo Franqui-Machin - University of Iowa
Kalyan Nadiminti - University of Iowa
Gregory S Thomas - University of Iowa
Mohamed E Salama - University Pathologists
Peter Altevogt - German Cancer Research Center
Gail Bishop - University of Iowa
Michael Tomasson - University of Iowa
Siegfried Janz - Medical College of Wisconsin
Jumei Shi - Tongji University
Lijuan Chen - Nanjing Medical University
Ivana Frech - University of Iowa
Guido Tricot - University of Iowa
Fenghuang Zhan - University of Iowa
Resource Type: Journal article
Publication Details: JNCI : Journal of the National Cancer Institute, Vol.112(5), pp.507-515
DOI: 10.1093/jnci/djz159
PMID: 31406992
PMCID: PMC7225664
NLM abbreviation: J Natl Cancer Inst
ISSN: 0027-8874
eISSN: 1460-2105
Publisher: Oxford University Press
Grant note: name: Leukemia & Lymphoma Society Translational Research Program; name: Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Cancer Research Program, award: W81XWH-19–1-0500; name: Myeloma Crowd Research Initiative; DOI: 10.13039/100001253, name: Multiple Myeloma Research Foundation; name: Cancer Center Support Grant National Institutes of Health, award: P30 CA086862, R21CA187388, R01CA151354; DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81529001, 81570190; DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81670199
Language: English
Date published: 05/01/2020
Academic Unit: Microbiology and Immunology; Anatomy and Cell Biology; President; Endodontics; Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Dental Research; Medicine Administration; Internal Medicine
Record Identifier: 9984284357002771

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