Pericentromeric Non-Coding DNA Transcription Is Associated with Niche Impairment in Patients with Ineffective or Partially Effective Multiple Myeloma Treatment
Mesenchymal stromal cells (MSC) ‘educated’ by tumor cells are an essential component of the multiple myeloma (MM) tumor microenvironment (TME) involved in tumor progression. Transcription of tandemly repeated (TR) non-coding DNA is often activated in many tumors and is required for tumor progression...
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2022-03-01
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| author | Natella I. Enukashvily Natalia Semenova Anna V. Chubar Dmitry I. Ostromyshenskii Ekaterina A. Gushcha Sergei Gritsaev Stanislav S. Bessmeltsev Viktor I. Rugal Egor M. Prikhodko Ivan Kostroma Anastasia Zherniakova Anastasia V. Kotova Liubov A. Belik Alexander Shumeev Irina I. Maslennikova Dmitry I. Ivolgin |
| author_facet | Natella I. Enukashvily Natalia Semenova Anna V. Chubar Dmitry I. Ostromyshenskii Ekaterina A. Gushcha Sergei Gritsaev Stanislav S. Bessmeltsev Viktor I. Rugal Egor M. Prikhodko Ivan Kostroma Anastasia Zherniakova Anastasia V. Kotova Liubov A. Belik Alexander Shumeev Irina I. Maslennikova Dmitry I. Ivolgin |
| author_sort | Natella I. Enukashvily |
| collection | DOAJ |
| description | Mesenchymal stromal cells (MSC) ‘educated’ by tumor cells are an essential component of the multiple myeloma (MM) tumor microenvironment (TME) involved in tumor progression. Transcription of tandemly repeated (TR) non-coding DNA is often activated in many tumors and is required for tumor progression and cancer cells genome reorganization. The aim of the work was to study functional properties including the TR DNA transcription profile of MSC from the hematopoietic niche of treated MM patients. Healthy donors (HD) and patients after bortezomib-based treatment (with partial or complete response, PoCR, and non-responders, NR) were enrolled in the study. Their trephine biopsies were examined histologically to evaluate the hematopoietic niche. MSC cultures obtained from the biopsies were used for evaluation of the proliferation rate, osteogenic differentiation, presence of tumor MSC markers, resistance to bortezomib, and pericentromeric TR DNA transcription level. The MSC ‘education’ by multiple myeloma cells was mimicked in co-culture experiments with or without bortezomib. The TR DNA transcription profile was accessed. The histological examination revealed the persistence of the tumor microenvironment (especially of the vasculature) in treated patients. In co-culture experiments, MSC of bortezomib-treated patients were more resistant to bortezomib and protected cancer MM cells of the RPMI8226 cell line more effectively than HD-MSC did. The MSC obtained from PoCR and NR samples differed in their functional properties (proliferation capacity, osteogenic potential, and cancer-associated fibroblasts markers). Transcriptome analysis revealed activation of the TR transcription in cells of non-hematopoietic origin from NR patients’ bone marrow. The pericentromeric TR DNA of HS2/HS3 families was among the most upregulated in stromal MSC but not in cancer cells. The highest level of transcription was observed in NR-MSC. Transcription of HS2/HS3 was not detected in healthy donors MSC unless they were co-cultured with MM cancer cells and acquired cancer-associated phenotype. Treatment with TNFα downregulated HS2/HS3 transcription in MSC and upregulated in MM cells. Our results suggest that the hematopoietic niche retains the cancer-associated phenotype after treatment. Pericentromeric non-coding DNA transcription is associated with the MSC cancer-associated phenotype in patients with ineffective or partially effective multiple myeloma treatment. |
| first_indexed | 2024-03-09T19:41:26Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-77252c3b498b4b9ca0597da04d0ae0b42023-11-24T01:38:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01236335910.3390/ijms23063359Pericentromeric Non-Coding DNA Transcription Is Associated with Niche Impairment in Patients with Ineffective or Partially Effective Multiple Myeloma TreatmentNatella I. Enukashvily0Natalia Semenova1Anna V. Chubar2Dmitry I. Ostromyshenskii3Ekaterina A. Gushcha4Sergei Gritsaev5Stanislav S. Bessmeltsev6Viktor I. Rugal7Egor M. Prikhodko8Ivan Kostroma9Anastasia Zherniakova10Anastasia V. Kotova11Liubov A. Belik12Alexander Shumeev13Irina I. Maslennikova14Dmitry I. Ivolgin15Lab of the Non-Coding DNA Studies, Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, RussiaClinical Department, Russian Research Institute of Hematology and Transfusiology FMBA of Russia, 191024 St. Petersburg, RussiaLab of the Non-Coding DNA Studies, Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, RussiaLab of the Non-Coding DNA Studies, Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, RussiaLab of the Non-Coding DNA Studies, Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, RussiaClinical Department, Russian Research Institute of Hematology and Transfusiology FMBA of Russia, 191024 St. Petersburg, RussiaClinical Department, Russian Research Institute of Hematology and Transfusiology FMBA of Russia, 191024 St. Petersburg, RussiaClinical Department, Russian Research Institute of Hematology and Transfusiology FMBA of Russia, 191024 St. Petersburg, RussiaPokrovsky Stem Cell Bank, LLC, 199106 St. Petersburg, RussiaClinical Department, Russian Research Institute of Hematology and Transfusiology FMBA of Russia, 191024 St. Petersburg, RussiaClinical Department, Russian Research Institute of Hematology and Transfusiology FMBA of Russia, 191024 St. Petersburg, RussiaLab of the Non-Coding DNA Studies, Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, RussiaLab of the Non-Coding DNA Studies, Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, RussiaPokrovsky Stem Cell Bank, LLC, 199106 St. Petersburg, RussiaCell Technologies Lab, North-Western State Medical University Named after I.I. Mechnikov, 191015 St. Petersburg, RussiaCell Technologies Lab, North-Western State Medical University Named after I.I. Mechnikov, 191015 St. Petersburg, RussiaMesenchymal stromal cells (MSC) ‘educated’ by tumor cells are an essential component of the multiple myeloma (MM) tumor microenvironment (TME) involved in tumor progression. Transcription of tandemly repeated (TR) non-coding DNA is often activated in many tumors and is required for tumor progression and cancer cells genome reorganization. The aim of the work was to study functional properties including the TR DNA transcription profile of MSC from the hematopoietic niche of treated MM patients. Healthy donors (HD) and patients after bortezomib-based treatment (with partial or complete response, PoCR, and non-responders, NR) were enrolled in the study. Their trephine biopsies were examined histologically to evaluate the hematopoietic niche. MSC cultures obtained from the biopsies were used for evaluation of the proliferation rate, osteogenic differentiation, presence of tumor MSC markers, resistance to bortezomib, and pericentromeric TR DNA transcription level. The MSC ‘education’ by multiple myeloma cells was mimicked in co-culture experiments with or without bortezomib. The TR DNA transcription profile was accessed. The histological examination revealed the persistence of the tumor microenvironment (especially of the vasculature) in treated patients. In co-culture experiments, MSC of bortezomib-treated patients were more resistant to bortezomib and protected cancer MM cells of the RPMI8226 cell line more effectively than HD-MSC did. The MSC obtained from PoCR and NR samples differed in their functional properties (proliferation capacity, osteogenic potential, and cancer-associated fibroblasts markers). Transcriptome analysis revealed activation of the TR transcription in cells of non-hematopoietic origin from NR patients’ bone marrow. The pericentromeric TR DNA of HS2/HS3 families was among the most upregulated in stromal MSC but not in cancer cells. The highest level of transcription was observed in NR-MSC. Transcription of HS2/HS3 was not detected in healthy donors MSC unless they were co-cultured with MM cancer cells and acquired cancer-associated phenotype. Treatment with TNFα downregulated HS2/HS3 transcription in MSC and upregulated in MM cells. Our results suggest that the hematopoietic niche retains the cancer-associated phenotype after treatment. Pericentromeric non-coding DNA transcription is associated with the MSC cancer-associated phenotype in patients with ineffective or partially effective multiple myeloma treatment.https://www.mdpi.com/1422-0067/23/6/3359multiple myelomamesenchymal stromal cellsmicrovesselstumor microenvironmentlong non-coding RNAhuman satellite 3 |
| spellingShingle | Natella I. Enukashvily Natalia Semenova Anna V. Chubar Dmitry I. Ostromyshenskii Ekaterina A. Gushcha Sergei Gritsaev Stanislav S. Bessmeltsev Viktor I. Rugal Egor M. Prikhodko Ivan Kostroma Anastasia Zherniakova Anastasia V. Kotova Liubov A. Belik Alexander Shumeev Irina I. Maslennikova Dmitry I. Ivolgin Pericentromeric Non-Coding DNA Transcription Is Associated with Niche Impairment in Patients with Ineffective or Partially Effective Multiple Myeloma Treatment International Journal of Molecular Sciences multiple myeloma mesenchymal stromal cells microvessels tumor microenvironment long non-coding RNA human satellite 3 |
| title | Pericentromeric Non-Coding DNA Transcription Is Associated with Niche Impairment in Patients with Ineffective or Partially Effective Multiple Myeloma Treatment |
| title_full | Pericentromeric Non-Coding DNA Transcription Is Associated with Niche Impairment in Patients with Ineffective or Partially Effective Multiple Myeloma Treatment |
| title_fullStr | Pericentromeric Non-Coding DNA Transcription Is Associated with Niche Impairment in Patients with Ineffective or Partially Effective Multiple Myeloma Treatment |
| title_full_unstemmed | Pericentromeric Non-Coding DNA Transcription Is Associated with Niche Impairment in Patients with Ineffective or Partially Effective Multiple Myeloma Treatment |
| title_short | Pericentromeric Non-Coding DNA Transcription Is Associated with Niche Impairment in Patients with Ineffective or Partially Effective Multiple Myeloma Treatment |
| title_sort | pericentromeric non coding dna transcription is associated with niche impairment in patients with ineffective or partially effective multiple myeloma treatment |
| topic | multiple myeloma mesenchymal stromal cells microvessels tumor microenvironment long non-coding RNA human satellite 3 |
| url | https://www.mdpi.com/1422-0067/23/6/3359 |
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