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Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma. J Natl Cancer Inst 2020 May 01;112(5):507-515

Date

08/14/2019

Pubmed ID

31406992

Pubmed Central ID

PMC7225664

DOI

10.1093/jnci/djz159

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.

Author List

Gao M, Bai H, Jethava Y, Wu Y, Zhu Y, Yang Y, Xia J, Cao H, Franqui-Machin R, Nadiminti K, Thomas GS, Salama ME, Altevogt P, Bishop G, Tomasson M, Janz S, Shi J, Chen L, Frech I, Tricot G, Zhan F

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin




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