Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics.
Stephan M TirierJan-Philipp MallmSimon SteigerAlexandra M PoosMohamed H S AwwadNicola GiesenNicola CasiraghiHana SusakKatharina BauerAnja BaumannLukas JohnAnja SeckingerDirk HoseCarsten Muller-TidowHartmut GoldschmidtOliver StegleMichael HundemerNiels WeinholdMarc-Steffen RaabKarsten RippePublished in: Nature communications (2021)
Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells 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 analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is 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.
Keyphrases
- single cell
- multiple myeloma
- rna seq
- bone marrow
- induced apoptosis
- high throughput
- cell cycle arrest
- copy number
- newly diagnosed
- end stage renal disease
- decision making
- ejection fraction
- acute myeloid leukemia
- stem cells
- endoplasmic reticulum stress
- signaling pathway
- chronic kidney disease
- dendritic cells
- oxidative stress
- transcription factor
- dna methylation
- pi k akt
- smoking cessation
- drug induced
- long non coding rna