Fig. 2: Transcriptional and genomic profiling of multiple myeloma in mice.
a, RNA-seq analyses of typical PC and B cell genes in PCs from mice at MGUS (n = 25) and MM (n = 40) stages versus control BM PCs (n = 6) and GC B cells (n = 3). TPM, transcripts per million. Boxes represent the median, upper and lower quartiles and whiskers represent minimum to maximum range. b, PCA of RNA-seq data from mouse and human MGUS and MM cells compared with control BM PCs. Human PCs were obtained from patients with newly diagnosed MGUS (n = 9) and MM (n = 41), and from BM aspirates from healthy donors (n = 7). c, PCA of RNA-seq data from BIcγ1 and MIcγ1 mice revealed two transcriptional modes of evolution during MM development. d, Quantitative PCR with reverse transcription (RT–qPCR) of mouse and human MYC gene expression in isolated BM PCs (n = 7), MGUS (n = 6) and MM (n = 12) cells from BIcγ1-derived and MGUS (n = 5) and MM (n = 14) cells from MIcγ1-derived mice. The mean and s.d. are represented. Kruskal–Wallis test P values adjusted for multiple comparisons by Dunn’s test are indicated. e, GSEA of RNA-seq data shows ‘MYC target genes’ at the top of the MM hallmarks in BIcγ1-related and MIcγ1 mice. NES, normalized enrichment score. f, Immunohistochemical image of BM sections revealed nuclear MYC protein expression in GFP+ MM cells from BIcγ1 mice (left). Western blot analysis revealed MYC expression in mouse MM-derived cell lines (right). g, MYC expression from RNA-seq data in samples from patients with MGUS (n = 8) or MM (n = 39) and in BM PCs (n = 7) from healthy donors. The mean ± s.d. is represented. Western blot analysis of MYC protein expression in human MM cell lines (right). h, Representative examples of spectral karyotyping analysis in metaphase cells from two MM-derived cell lines. i, Copy number variation and WES analyses of primary cells from mice with MGUS and MM and in an MM-derived cell line. j, WGS mapped the breakpoints in two chromosomal translocations between the Igh or Igl and MYC genes in MM9275 and MM5080 cell lines, respectively. k, MYC targeting with the MYC inhibitor MYCi975 reduced MYC expression (right) and decreased MM cell viability (left) in mouse and human MM cells. Data corresponding to the mean ± s.e.m. from two or three independent experiments are represented for each cell line. *P < 0.05; **P < 0.01; ***P < 0.001.
