Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma. J Natl Cancer Inst 2020 May 01;112(5):507-515
Date
08/14/2019Pubmed ID
31406992Pubmed Central ID
PMC7225664DOI
10.1093/jnci/djz159Scopus ID
2-s2.0-85084784202 (requires institutional sign-in at Scopus site) 32 CitationsAbstract
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 FAuthor
Siegfried Janz MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCD24 Antigen
Carcinogenesis
Cell Self Renewal
Drug Resistance, Neoplasm
Female
Heterografts
Humans
Male
Mice
Mice, Inbred NOD
Multiple Myeloma
Neoplastic Stem Cells
