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J Natl Cancer Inst. 2019 Aug 12. pii: djz159. doi: 10.1093/jnci/djz159. [Epub ahead of print]

Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma.

Author information

Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, Iowa City, IA, USA.
Department of Pathology, University of Utah, and Associated Regional University Pathologists (ARUP) Laboratories, Salt Lake City, Utah, USA.
G-300-Oncodermatology, German Cancer Research Center (DKFZ), Heidelberg, Germany, Europe.
Department of Microbiology and Immunology, University of Iowa and VA Medical Center, Iowa City, IA, USA.
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.



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 non-cycling or slowly-cycling and very drug-resistant.


Gene expression profiling and qRT-PCR were employed to define genes differentially expressed between the side-population (SP) cells, which contains 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 3-6 mice per group.


CD24 was highly expressed in the SP cells and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell (iPS/ES) genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = 3 of 5 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 (CR) MM samples with persistent minimal residual disease (MRD) compared to 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 (HR = 3.81, 95% 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.


Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.


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