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Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma. J Natl Cancer Inst 2019 Aug 12

Date

08/14/2019

Pubmed ID

31406992

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 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.

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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