Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression

The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies

Supplementary Data 4 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

Gene expression associated with BATF in NDMM bone marrow CoMMpass samples</p

Supplementary Table 2 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

Primers</p

Supplementary Data 2 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

GSEA Hallmark Gene Sets</p

Supplementary Data 5 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

GSEA of genes associated with BATF expression in CoMMpass</p

Supplementary Table 1 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

Multi-variate analysis of BATF, BATF2, and BATF3 expression</p

Supplementary Data 1 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

Differentially expressed genes between POM (200 nM), GNE781 (40nM) or both (Combo) in JJN3 and KMS11 control (eGFP) and BATF overexpressing cells</p

Supplementary Data 3 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

Differential Accessible Regions in JJN3 and KMS11</p

Supplementary Figures S1-S11 from Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

Supplementary Figures 1-11, which support data and conclusions provided in the main figures</p