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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

1
Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
2
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
3
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
4
Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, Iowa City, IA, USA.
5
Department of Pathology, University of Utah, and Associated Regional University Pathologists (ARUP) Laboratories, Salt Lake City, Utah, USA.
6
G-300-Oncodermatology, German Cancer Research Center (DKFZ), Heidelberg, Germany, Europe.
7
Department of Microbiology and Immunology, University of Iowa and VA Medical Center, Iowa City, IA, USA.
8
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

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

METHODS:

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.

RESULTS:

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.

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.

PMID:
31406992
DOI:
10.1093/jnci/djz159

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