Related Experiment Video
Updated: Jun 16, 2025
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
Multiple myeloma with 1q gain/amplification exhibits reduced CD38 expression via interleukin-6 receptor
Wataru Kuroki1, Akihiro Kitadate1, Yuto Takahashi2
1Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
Abstract:
Multiple myeloma (MM) with chromosome 1q21 gain/amplification (1q+) has been reported to respond poorly to daratumumab. We aimed to explore the mechanism of daratumumab resistance in 1q+ MM. Our findings revealed significantly lower CD38 expression in patients with 1q+ MM than in those with 1q wild type (WT) MM. Next, we focused on the interleukin-6 receptor (IL6R) located in the 1q21 region because a previous report shows that interleukin-6 (IL-6) reduces CD38 expression via the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway activation in MM. Indeed, IL6R expression was significantly higher in 1q+ MM than in 1q WT MM. We verified that the 1q+ human myeloma cell lines (HMCLs) expressed higher IL6R levels than the 1q WT HMCLs. IL-6 treatment induced CD38 downregulation in both the 1q+ HMCLs and primary bone marrow (BM) samples but not in their 1q WT HMCLs and BM samples. IL-6 also resulted in the upregulation of phosphorylated STAT3 in 1q+ HMCLs but not in the 1q WT HMCLs. Furthermore, inhibition of the IL-6/JAK/STAT pathway by treatment with ruxolitinib or tocilizumab restored CD38 expression in the 1q+ HMCLs and BM samples. These findings elucidate the mechanisms underlying daratumumab resistance in 1q+ MM and provide insights for future therapeutic strategies.
Insights
Multiple myeloma with 1q+ chromosome gain shows poor response to daratumumab due to lower CD38 expression. Targeting the IL-6/JAK/STAT pathway can restore CD38 levels, overcoming resistance in 1q+ multiple myeloma.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Multiple myeloma (MM) with chromosome 1q21 gain/amplification (1q+) is associated with poor outcomes.
- Daratumumab, a CD38-targeting antibody, is less effective in 1q+ MM patients.
- The underlying mechanisms of daratumumab resistance in 1q+ MM require elucidation.
Purpose of the Study:
- To investigate the mechanisms of daratumumab resistance in 1q+ multiple myeloma.
- To explore the role of CD38 expression and the IL-6/JAK/STAT pathway in 1q+ MM resistance.
Main Methods:
- Comparative analysis of CD38 and IL6R expression in 1q+ versus 1q wild-type (WT) MM.
- In vitro studies using human myeloma cell lines (HMCLs) and primary bone marrow (BM) samples.
- Assessment of IL-6 treatment effects on CD38 and STAT3 phosphorylation.
- Evaluation of IL-6/JAK/STAT pathway inhibitors (ruxolitinib, tocilizumab) on CD38 expression.
Main Results:
- Patients with 1q+ MM exhibited significantly lower CD38 expression compared to 1q WT MM.
- IL6R expression was significantly higher in 1q+ MM, located in the 1q21 region.
- IL-6 treatment downregulated CD38 expression and upregulated phosphorylated STAT3 in 1q+ MM cells and samples.
- Inhibition of the IL-6/JAK/STAT pathway restored CD38 expression in 1q+ MM.
Conclusions:
- Reduced CD38 expression, driven by increased IL-6 receptor signaling via the IL-6/JAK/STAT pathway, contributes to daratumumab resistance in 1q+ MM.
- Targeting the IL-6/JAK/STAT pathway presents a potential therapeutic strategy to overcome daratumumab resistance in 1q+ MM.
- These findings offer critical insights for developing novel treatment approaches for refractory 1q+ multiple myeloma.
