Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics
Abstract 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)....
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/fa70b923d8a843a39ddf7f12f81781e7 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:fa70b923d8a843a39ddf7f12f81781e7 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:fa70b923d8a843a39ddf7f12f81781e72021-12-05T12:21:44ZSubclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics10.1038/s41467-021-26951-z2041-1723https://doaj.org/article/fa70b923d8a843a39ddf7f12f81781e72021-11-01T00:00:00Zhttps://doi.org/10.1038/s41467-021-26951-zhttps://doaj.org/toc/2041-1723Abstract 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.Stephan M. TirierJan-Philipp MallmSimon SteigerAlexandra M. PoosMohamed H. S. AwwadNicola GiesenNicola CasiraghiHana SusakKatharina BauerAnja BaumannLukas JohnAnja SeckingerDirk HoseCarsten Müller-TidowHartmut GoldschmidtOliver StegleMichael HundemerNiels WeinholdMarc S. RaabKarsten RippeNature PortfolioarticleScienceQENNature Communications, Vol 12, Iss 1, Pp 1-16 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Science Q |
| spellingShingle |
Science Q Stephan M. Tirier Jan-Philipp Mallm Simon Steiger Alexandra M. Poos Mohamed H. S. Awwad Nicola Giesen Nicola Casiraghi Hana Susak Katharina Bauer Anja Baumann Lukas John Anja Seckinger Dirk Hose Carsten Müller-Tidow Hartmut Goldschmidt Oliver Stegle Michael Hundemer Niels Weinhold Marc S. Raab Karsten Rippe Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics |
| description |
Abstract 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. |
| format |
article |
| author |
Stephan M. Tirier Jan-Philipp Mallm Simon Steiger Alexandra M. Poos Mohamed H. S. Awwad Nicola Giesen Nicola Casiraghi Hana Susak Katharina Bauer Anja Baumann Lukas John Anja Seckinger Dirk Hose Carsten Müller-Tidow Hartmut Goldschmidt Oliver Stegle Michael Hundemer Niels Weinhold Marc S. Raab Karsten Rippe |
| author_facet |
Stephan M. Tirier Jan-Philipp Mallm Simon Steiger Alexandra M. Poos Mohamed H. S. Awwad Nicola Giesen Nicola Casiraghi Hana Susak Katharina Bauer Anja Baumann Lukas John Anja Seckinger Dirk Hose Carsten Müller-Tidow Hartmut Goldschmidt Oliver Stegle Michael Hundemer Niels Weinhold Marc S. Raab Karsten Rippe |
| author_sort |
Stephan M. Tirier |
| title |
Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics |
| title_short |
Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics |
| title_full |
Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics |
| title_fullStr |
Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics |
| title_full_unstemmed |
Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics |
| title_sort |
subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/fa70b923d8a843a39ddf7f12f81781e7 |
| work_keys_str_mv |
AT stephanmtirier subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT janphilippmallm subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT simonsteiger subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT alexandrampoos subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT mohamedhsawwad subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT nicolagiesen subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT nicolacasiraghi subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT hanasusak subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT katharinabauer subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT anjabaumann subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT lukasjohn subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT anjaseckinger subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT dirkhose subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT carstenmullertidow subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT hartmutgoldschmidt subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT oliverstegle subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT michaelhundemer subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT nielsweinhold subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT marcsraab subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics AT karstenrippe subclonespecificmicroenvironmentalimpactanddrugresponseinrefractorymultiplemyelomarevealedbysinglecelltranscriptomics |
| _version_ |
1718372053373943808 |