CD24+ and CD24C MM cells were injected subcutaneously into the right and left flanks of NOD-Rag1null mice. 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 main 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 experienced substandard progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, = .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. The GR-203040 malignancy stem cell theory recognizes a rare populace of cells unique from bulk tumor cells with the ability to initiate and propagate tumors. This very limited populace is usually further distinguished by pluripotency, self-renewal capacity, and resistance to chemotherapy and radiotherapy. These tumor-initiating cells (TICs), also known as malignancy stem cells, give rise to differentiated progeny leading to heterogeneity of tumors, whereby differentiated malignancy cells can dedifferentiate to TICs. TICs were originally documented and explained in acute myeloid leukemia (1,2) and, in the past 20?years, have been identified in a growing number both of hematologic and sound tumors (3C6). GR-203040 Multiple myeloma (MM) is a plasma cell malignancy defined by bone, renal, immunological, and hematological complications. Although autologous stem cell transplantation in combination with novel drug regimens has greatly improved patient outcomes, the majority of MM patients die of their disease after relapse. The high frequency of relapse suggests the persistence of a treatment-resistant populace (7,8). Furthermore, normal polyclonal plasma cells actively secrete intact immunoglobulins both with and light chains (9,10), and MM is usually characterized by an excess of clonotypic plasma cells that express either or light chains (11), supporting a clonal origin of MM tumor cells. Still, identifying a consensus TIC phenotype has remained elusive in MM. MM side-population (SP) cells, which are considered a functional surrogate GR-203040 marker for malignancy stem cells, generate more colonies compared with mature MM cells and may lack CD138 expression (12,13). Possible stem cell populations include light-chain (LC)- restricted cells with a CD138C/CD19+/CD27+ phenotype (8,14,15), CD138+/CD34+/B7CH1+ subpopulations (16), and CD38++/CD45C plasma cells (17C19). The human cell surface antigen CD24 is a sialoglycoprotein localized in membrane lipid raft domains (20). As a heat-stable antigen, CD24 has been used as a marker to identify hematopoietic cells, neuronal cells, and B lymphocytes (21,22). Previous studies have found that CD24 is a TIC marker in multiple cancers, including liver, ovarian, and pancreatic (23C26). Because of the persistence of GR-203040 clonal plasma cells for more than 10?years in MM patients in complete remission (CR) with minimal residual disease (MRD) (27), we hypothesized that at least some of the MM cells in these patients had TIC features. Here, we performed a systematic analysis to identify and characterize this Rabbit Polyclonal to DNAJC5 rare TIC populace using main MM samples and MM cell lines. Methods Patient Samples Deidentified clinical bone marrow (BM) aspirates were obtained from 137 MM patients at the University or college of Iowa and the Nanjing Medical University or college. Studies were approved by the institutional review boards at each institution. Written informed consent was obtained in accordance with the Declaration of.