ENAGenomicsChromatin Networks, German Cancer Research Centerhttps://www.ebi.ac.uk/ena/browser/view/PRJNA679548Homo sapiensVirtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we have analyzed the heterogeneous tumor cell population of 20 RRMM patients and its complex interaction network with the BME by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain expressed a specific transcriptomic signature and frequently expanded during treatment. Furthermore, RRMM cells shaped an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It was characterized by the accumulation of PD1+ γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making. Overall design: Single cell RNA-seq of tumor cells and bone marrow microenvironment in relapsed/refractory multiple myeloma, **The submitter declares that the raw data were deposited to EGA (EGAS00001004805) due to data protection regulations.**ENAd230, Multiple myeloma (disorder), Kahler's disease, Cell Myelomas, dTAFII250, Ximpact, Myeloma-Multiples, EfW1, Myeloma-Multiple, plasma cell, dmTAF[[II]]230, Multiple Myelomas, myelomatosis, dmTAF1, Taf230, myeloid neoplasm of plasma cell, responsivity, [M]Plasma cell myeloma, Myelomatoses, TAF250, Plasmacytic myeloma, systemic, reactivity, amyloidosis, Taf200, Multiple myeloma, dTAF[[II]]250, TFIID TAF250, cel, cell, Somatic mutation, Plasma Cell Myelomas, myeloma, Taf1p, dTAF250, drugs, resistance to, Cell Myeloma, medicine, no ICD-O subtype (morphologic abnormality), plasma cell myeloma, TAF, Plasma Cell, myeloma - multiple, Plasma-Cell Myelomas, Plasma-cell myeloma, Disease, dTAF[[II]]230, TAF[[II]]250, Myelomas, Myeloma, malignant, drug, TAF200, l(3)84Ab, Myeloma Multiple, BG:DS00004.13, TAFII-250, TAF250/230, impact-a, Cell, Multiple Myeloma, MM, dTAF230, Al amyloidosis, multiple myeloma, Kahler, TAFII250, p230, TAF[[II]]250/230, TFIID, NOS, Myelomatosis, multiple myeloma/plasma cell myeloma, MULT MYELM W/O REMISSION, morphology (morphologic abnormality), Plasma-Cell, Plasma-Cell Myeloma, Plasma, Taf[[II]]250, TAF[[II]]230, susceptibility to, Kahler Disease, TAF[II]250, CG17603, TAF[[II]], medullary plasmacytoma, Multiple myeloma without mention of remission, Multiple, DmelCG17603, no ICD-O subtype, multiple, TAF1., Plasma Cell Myeloma, Taf250, SR3-5, response, Multiple myeloma (clinical), E430016J11Rik, RWDD5, Kahler disease, TAF230, plasma cell myeloid neoplasmd230, Multiple myeloma (disorder), Kahler's disease, Cell Myelomas, dTAFII250, Ximpact, Myeloma-Multiples, EfW1, Myeloma-Multiple, plasma cell, dmTAF[[II]]230, Multiple Myelomas, myelomatosis, dmTAF1, Taf230, myeloid neoplasm of plasma cell, responsivity, [M]Plasma cell myeloma, Myelomatoses, TAF250, Plasmacytic myeloma, systemic, reactivity, amyloidosis, Taf200, Multiple myeloma, dTAF[[II]]250, TFIID TAF250, cel, cell, Somatic mutation, Plasma Cell Myelomas, myeloma, Taf1p, dTAF250, drugs, resistance to, Cell Myeloma, medicine, no ICD-O subtype (morphologic abnormality), plasma cell myeloma, TAF, Plasma Cell, myeloma - multiple, Plasma-Cell Myelomas, Plasma-cell myeloma, Disease, dTAF[[II]]230, TAF[[II]]250, Myelomas, Myeloma, malignant, drug, TAF200, l(3)84Ab, Myeloma Multiple, BG:DS00004.13, TAFII-250, TAF250/230, impact-a, Cell, Multiple Myeloma, MM, dTAF230, Al amyloidosis, multiple myeloma, Kahler, TAFII250, p230, TAF[[II]]250/230, TFIID, NOS, Myelomatosis, multiple myeloma/plasma cell myeloma, MULT MYELM W/O REMISSION, morphology (morphologic abnormality), Plasma-Cell, Plasma-Cell Myeloma, Plasma, Taf[[II]]250, TAF[[II]]230, susceptibility to, Kahler Disease, TAF[II]250, CG17603, TAF[[II]], medullary plasmacytoma, Multiple myeloma without mention of remission, Multiple, DmelCG17603, no ICD-O subtype, multiple, TAF1., Plasma Cell Myeloma, Taf250, SR3-5, response, Multiple myeloma (clinical), E430016J11Rik, RWDD5, Kahler disease, TAF230, plasma cell myeloid neoplasm0.00.00.00.00.0falseSubclone specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single cell transcriptomicsSubclone specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single cell transcriptomics2022-05-122021-08-20PRJNA679548GSE161801348451889606