CD34+ myeloma cells with self-renewal activities are therapy-resistant and persist as MRD in cell cycle quiescence

• Published in: International journal of hematology Vol. 115; no. 3; pp. 336 - 349
• Main Authors: Serizawa, Kentaro, Tanaka, Hirokazu, Ueda, Takeshi, Fukui, Ayano, Kakutani, Hiroaki, Taniguchi, Takahide, Inoue, Hiroaki, Kumode, Takahiro, Taniguchi, Yasuhiro, Rai, Shinya, Hirase, Chikara, Morita, Yasuyoshi, Espinoza, J. Luis, Tatsumi, Yoichi, Ashida, Takashi, Matsumura, Itaru
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.03.2022; Springer Nature B.V
• Subjects: Animals; Antigens, CD34 - genetics; Antigens, CD34 - metabolism; CD34 antigen; Cell Cycle; Cell Self Renewal; Cell surface; Drug Resistance, Neoplasm; Female; Gene Expression - genetics; Hematology; Humans; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, Knockout; Minimal residual disease; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Neoplasm Transplantation; Neoplasm, Residual - pathology; Oncology; Original Article; Surface markers; Therapy; Tumor Cells, Cultured; Xenografts; Xenotransplantation; Self-renewal; Measurable residual disease; Multiple myeloma; Cell cycle; Side population
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-021-03261-0

Side population (SP) is known to include therapy-resistant cells in various cancers. Here, we analyzed SP using multiple myeloma (MM) samples. The SP accounted for 2.96% in MM cells from newly diagnosed MM (NDMM). CD34 was expressed in 47.8% of SP cells, but only in 2.11% of bulk MM cells. CD34 + MM cells expressed more immature cell surface markers and a gene signature than CD34 − MM cells. CD34 + but not CD34 − MM cells possessed clonogenic activities and showed long-term self-renewal activities in xenotransplantation assays. Similarly, whereas 2.20% of MM cells were CD34 + in NDMM ( n  = 38), this proportion increased to 42.6% in minimal residual disease (MRD) samples ( n  = 16) ( p  < 0.001) and to 17.7% in refractory/relapsed MM (RRMM) ( n  = 30) ( p  < 0.01). Cell cycle analysis showed that 24.7% of CD34 + MM cells from NDMM were in G0 phase while this proportion was 54.9% in MRD ( p  < 0.05) and 14.5% in RRMM, reflecting the expansion of MM. Together, CD34 + MM cells with long-term self-renewal activities persist as MRD in cell cycle quiescence or remain as therapy-resistant cells in RRMM, substantiating the necessity of targeting this population to improve clinical outcomes of MM.