Fig. 1: Genetically heterogeneous mouse models of human-like multiple myeloma.
a, Schematic of the genetic screen strategy, whereby transgenic mice were crossed with cγ1-cre or mb1-cre mice. Among 31 genetically heterogeneous mouse lines generated, MImb1, MIcγ1 and BIcγ1 strains developed MM. GEM, genetically engineered mice; m, months. b, Kaplan–Meier OS curves of MImb1, MIcγ1, BIcγ1, control (YFPcγ1 and YFPmb1) and Vk*MYC mice. c, Representative flow cytometry analysis in the BM of BIcγ1 mice at the time of death, which shows an increased number of GFP+CD138+B220−sIgM− MM cells. d, Giemsa staining of a representative BM sample in BIcγ1 mice revealed human-like PCs with expression of acid phosphatase (AP; left). On the right, immunohistochemical examination in BIcγ1 mice revealed CD138 surface expression by MM cells. e, MM cells show increased surface expression of Bcma, Slamf7 and Taci according to flow cytometry analyses. f, Representative electrophoresis of immunoglobulin secretion in serum samples from MImb1, MIcγ1 and BIcγ1 mice shows M spikes corresponding to the gamma fraction. g, Quantification of immunoglobulin isotypes in serum samples by ELISA in MImb1 (n = 3), MIcγ1 (n = 2), BIcγ1 (n = 4) and YFPcγ1 control (n = 9) mice. h, Kaplan–Meier survival curves of mouse lines that develop MM derived from the BIcγ1 strain with additional KRASG12D mutation, heterozygous Trp53 deletion, or expression of cyclin D1, c-MAF or MMSET. i, Kaplan–Meier survival curves of mouse lines that develop MM derived from MIcγ1 mice with additional KRASG12D mutation, heterozygous Trp53 deletion, c-MAF expression or BCL2 expression. j, Kaplan–Meier survival curves in mice with MMSET/NSD2 expression crossed with lines carrying either IKK2NF-κB activation or c-MYC expression, which developed MM at old ages. k, Flow cytometry analyses in BIcγ1 and MIcγ1 mice revealed that precursor states precede clinically evident MM in genetically heterogeneous mice. l, Analysis of Igh clonality according to RNA-seq of immunoglobulin gene loci and classification by the presence of explicit clonotypes for each sample. B cell receptor (BCR) repertoires and the most expanded clone groups in control, MGUS and MM samples. Log-rank (Mantel–Cox) test was used. *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant.
