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Acknowledgements
We thank Professor Takemi Otsuki (Kawasaki Medical School, Kurashiki, Japan) for the kind gift of MM cell lines. This work was supported in part by Grants-in-Aid for Scientific Research, # 20K08763 and #17K09940 (both Y.H.) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (Y.H.), grants-in-aid from the Translational Research Network Program of Japan Agency for Medical Research and Development (AMED) #15lm0103010j0002 and #16lm0103010j0003 (both Y.H.) and the Japanese Society of Hematology Research Grant (Y.H.).
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YH designed the study, established cell lines, interpreted the data, wrote the paper and supervised the research. TF examined integrin expression and drug resistance and conducted RNA sequence analysis. RU examined the expression of CRBN-axis proteins and drug sensitivity. DI conducted flow cytometry. Tak.Y helped in the early stages of the study. Tom.Y performed survival analysis and the statistical evaluation. MM reviewed the manuscript. MH provided the patient samples and the clinical data.
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The authors of this manuscript have the following conflicts of interests: research grants from Takeda Pharmaceutical Company (Y.H.), MSD (Y.H.), Astellas Pharma Inc. (Y.H.), Daiichi Sankyo Co. LD (Y.H.), Pfizer Inc. (Y.H.), Ono Pharmaceutical Co. LD (Y.H.).
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12185_2022_3297_MOESM1_ESM.tif
Supplementary file1 Recovery of lenalidomide sensitivity by drug washout. Lenalidomide sensitivity was not recovered by drug washout. KMS21R, MUM24R, KMS27R and KMS34R cells were cultured under lenalidomide-free condition for over 30 days and were thence designated KMS21RF, MUM24RF, KMS27RF and KMS34RF cells, respectively. Viability of myeloma cells examined by WST-1 assay (TIF 91 KB)
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Supplementary file2 Resistance of lenalidomide-exposed cells to other classes of anti-myeloma drugs. Resistance to the anti-myeloma drugs bortezomib (Bor) and panobinostat (Pano) was examined by WST-1 assay in lenalidomide-exposed cells (Roche Diagnostics, Basel, Switzerland). *p < 0.05 by Student’s t test (PDF 62 KB)
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Supplementary file3 RNA sequence. a RNA sequencing and functional annotation clustering were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID 6.8; https://david.ncifcrf.gov/) (Hokkaido System Science, Sapporo, Japan). Ensembl Genome Browser (https://asia.ensembl.org/index.html) was used for reference genome information. A total of 301 genes that were expressed at least four times higher in MUM24R than in MUM24 cells and had FPKM (fragments per kilo base of exon per million mapped fragments) values ≥ 0.01 were identified and classified based on the gene ontology. Shown are the 25 clusters in which p values (−log10) were ≥ 0.05. b TPM values for gene expression level in RNA sequences of MUM24 and MUM24R cells are shown. For reference, RNA sequence data for KMS21, KMS21R, KMS27, KMS27R and KMS34 and KMS34R are available at GSE165557 with accession numbers GSM5039297-GSM5039302, respectively. These analyses were performed in different laboratories at different times from MUM24 cells. c DAVID analyses of KMS21R, KMS27R and KMS34R cells were done under the same conditions described in a. Red asterisks indicate “cell adhesion” or related clusters and/or “integrin-mediated signaling pathway.” Gene ontology and KEGG were used for KMS21R and KMS27R and for KMS34R, respectively (PDF 61 KB)
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Supplementary file5 Cell surface expressions of integrins. Myeloma cells were incubated with or without 30 µM lenalidomide at 37˚C for 24 h. After treatment with clear back (#MTG-001, MBL Tokyo), cell surface expressions of integrins β5 and β7 were examined by flow cytometry (LSR II, BD Biosciences Franklin Lakes, NJ USA) using PE-anti-human ITGB5 antibody (#345203, BioLegend, San Diego, USA) and APC-anti-human ITGB7 antibody (#321207, BioLegend). Antibody information is summarized in Table S1 (PDF 1821 KB)
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Supplementary file6 Morphological changes in KMS27R cells after long-term exposure to lenalidomide. After long-term exposure of KMS27 cells to low dose (3 μM) lenalidomide, some KMS27R cells adhered to the culture flask and showed spindle-like morphology (red arrow), while all parental KMS27 cells grew floating and partly formed crumps (yellow triangle) (PDF 5559 KB)
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Hattori, Y., Futo, T., Uozaki, R. et al. Integrin β5 and β7 expression in lenalidomide-resistant multiple myeloma cells. Int J Hematol 115, 605–608 (2022). https://doi.org/10.1007/s12185-022-03297-w
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DOI: https://doi.org/10.1007/s12185-022-03297-w