Skip to main content

Advertisement

SpringerLink
Log in

Mesenchymal stromal cell senescence in haematological malignancies

  • Non-Thematic Review
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), and multiple myeloma (MM) are age-related haematological malignancies with defined precursor states termed myelodysplastic syndrome (MDS), monoclonal B-cell lymphocytosis (MBL), and monoclonal gammopathy of undetermined significance (MGUS), respectively. While the progression from asymptomatic precursor states to malignancy is widely considered to be mediated by the accumulation of genetic mutations in neoplastic haematopoietic cell clones, recent studies suggest that intrinsic genetic changes, alone, may be insufficient to drive the progression to overt malignancy. Notably, studies suggest that extrinsic, microenvironmental changes in the bone marrow (BM) may also promote the transition from these precursor states to active disease. There is now enhanced focus on extrinsic, age-related changes in the BM microenvironment that accompany the development of AML, CLL, and MM. One of the most prominent changes associated with ageing is the accumulation of senescent mesenchymal stromal cells within tissues and organs. In comparison with proliferating cells, senescent cells display an altered profile of secreted factors (secretome), termed the senescence-associated-secretory phenotype (SASP), comprising proteases, inflammatory cytokines, and growth factors that may render the local microenvironment favourable for cancer growth. It is well established that BM mesenchymal stromal cells (BM-MSCs) are key regulators of haematopoietic stem cell maintenance and fate determination. Moreover, there is emerging evidence that BM-MSC senescence may contribute to age-related haematopoietic decline and cancer development. This review explores the association between BM-MSC senescence and the development of haematological malignancies, and the functional role of senescent BM-MSCs in the development of these cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

References

  1. Welch, J. S., Ley, T. J., Link, D. C., Miller, C. A., Larson, D. E., Koboldt, D. C., Wartman, L. D., Lamprecht, T. L., Liu, F., Xia, J., Kandoth, C., Fulton, R. S., McLellan, M. D., Dooling, D. J., Wallis, J. W., Chen, K., Harris, C. C., Schmidt, H. K., Kalicki-Veizer, J. M., Lu, C., et al. (2012). The origin and evolution of mutations in acute myeloid leukemia. Cell, 150(2), 264–278. https://doi.org/10.1016/j.cell.2012.06.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Steensma, D. P., Bejar, R., Jaiswal, S., Lindsley, R. C., Sekeres, M. A., Hasserjian, R. P., & Ebert, B. L. (2015). Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood, 126(1), 9–16. https://doi.org/10.1182/blood-2015-03-631747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P., Mar, B. G., Lindsley, R. C., Mermel, C., Burtt, N., Chavez, A., Higgins, J. M., Moltchanov, V., Kinnunen, L., Koistinen, H., Ladenvall, C., Getz, G., Correa, A., Gabriel, S., Kathiresan, S., Stringham, H., et al. (2014). Clonal hematopoiesis with somatic mutations is a common, age-related condition associated with adverse outcomes. Blood, 124(21), 840. https://doi.org/10.1056/NEJMoa1408617

    Article  Google Scholar 

  4. Young, A. L., Challen, G. A., Birmann, B. M., & Druley, T. E. (2016). Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nature Communucations, 7, 12484. https://doi.org/10.1038/ncomms12484

    Article  CAS  Google Scholar 

  5. Veiga, C. B., Lawrence, E. M., Murphy, A. J., Herold, M. J., & Dragoljevic, D. (2021). Myelodysplasia syndrome, clonal hematopoiesis and cardiovascular disease. Cancers, 13(8), 1968. https://doi.org/10.3390/cancers13081968

  6. Strati, P., & Shanafelt, T. D. (2015). Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: Diagnosis, natural history, and risk stratification. Blood, 126(4), 454–462. https://doi.org/10.1182/blood-2015-02-585059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kyle, R. A., Larson, D. R., Therneau, T. M., Dispenzieri, A., Kumar, S., Cerhan, J. R., & Rajkumar, S. V. (2018). Long-term follow-up of monoclonal gammopathy of undetermined significance. New England Journal of Medicine, 378(3), 241–249. https://doi.org/10.1056/NEJMoa1709974

    Article  CAS  PubMed  Google Scholar 

  8. Genovese, G., Kahler, A. K., Handsaker, R. E., Lindberg, J., Rose, S. A., Bakhoum, S. F., Chambert, K., Mick, E., Neale, B. M., Fromer, M., Purcell, S. M., Svantesson, O., Landen, M., Hoglund, M., Lehmann, S., Gabriel, S. B., Moran, J. L., Lander, E. S., Sullivan, P. F., Sklar, P., et al. (2014). Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. New England Journal of Medicine, 371(26), 2477–2487. https://doi.org/10.1056/NEJMoa1409405

    Article  CAS  PubMed  Google Scholar 

  9. Ma, X., Does, M., Raza, A., & Mayne, S. T. (2007). Myelodysplastic syndromes: Incidence and survival in the United States. Cancer, 109(8), 1536–1542. https://doi.org/10.1002/cncr.22570

    Article  PubMed  Google Scholar 

  10. Shim, Y. K., Middleton, D. C., Caporaso, N. E., Rachel, J. M., Landgren, O., Abbasi, F., Raveche, E. S., Rawstron, A. C., Orfao, A., Marti, G. E., & Vogt, R. F. (2010). Prevalence of monoclonal B-cell lymphocytosis: a systematic review. Cytometry. Part B: Clinical Cytometry, 78. https://doi.org/10.1002/cyto.b.20538

  11. Kyle, R. A., Therneau, T. M., Rajkumar, S. V., Larson, D. R., Plevak, M. F., Offord, J. R., Dispenzieri, A., Katzmann, J. A., & Melton, L. J., 3rd. (2006). Prevalence of monoclonal gammopathy of undetermined significance. New England Journal of Medicine, 354(13), 1362–1369. https://doi.org/10.1056/NEJMoa054494

    Article  CAS  PubMed  Google Scholar 

  12. Costa, L. J., Brill, I. K., Omel, J., Godby, K., Kumar, S. K., & Brown, E. E. (2017). Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States. Blood Advances, 1(4), 282–287. https://doi.org/10.1182/bloodadvances.2016002493

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hallek, M., Shanafelt, T. D., & Eichhorst, B. (2018). Chronic lymphocytic leukaemia. Lancet, 391(10129), 1524–1537. https://doi.org/10.1016/S0140-6736(18)30422-7

    Article  PubMed  Google Scholar 

  14. Oran, B., & Weisdorf, D. J. (2012). Survival for older patients with acute myeloid leukemia: A population-based study. Haematologica, 97(12), 1916–1924. https://doi.org/10.3324/haematol.2012.066100

    Article  PubMed  PubMed Central  Google Scholar 

  15. Rozhok, A. I., Salstrom, J. L., & DeGregori, J. (2014). Stochastic modeling indicates that aging and somatic evolution in the hematopoetic system are driven by non-cell-autonomous processes. Aging, 6(12), 1033–1048. https://doi.org/10.18632/aging.100707

    Article  PubMed  PubMed Central  Google Scholar 

  16. Dutta, A. K., Fink, J. L., Grady, J. P., Morgan, G. J., Mullighan, C. G., To, L. B., Hewett, D. R., & Zannettino, A. C. W. (2019). Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterised by clonal stability. Leukemia, 33(2), 457–468. https://doi.org/10.1038/s41375-018-0206-x

    Article  CAS  PubMed  Google Scholar 

  17. Das, R., Strowig, T., Verma, R., Koduru, S., Hafemann, A., Hopf, S., Kocoglu, M. H., Borsotti, C., Zhang, L., Branagan, A., Eynon, E., Manz, M. G., Flavell, R. A., & Dhodapkar, M. V. (2016). Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice. Nature Medicine, 22(11), 1351–1357. https://doi.org/10.1038/nm.4202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Medyouf, H., Mossner, M., Jann, J.-C., Nolte, F., Raffel, S., Herrmann, C., Lier, A., Eisen, C., Nowak, V., Zens, B., Müdder, K., Klein, C., Obländer, J., Fey, S., Vogler, J., Fabarius, A., Riedl, E., Roehl, H., Kohlmann, A., Staller, M., et al. (2014). Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell, 14(6), 824–837. https://doi.org/10.1016/j.stem.2014.02.014

    Article  CAS  PubMed  Google Scholar 

  19. Balderman, S. R., Li, A. J., Hoffman, C. M., Frisch, B. J., Goodman, A. N., LaMere, M. W., Georger, M. A., Evans, A. G., Liesveld, J. L., Becker, M. W., & Calvi, L. M. (2016). Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome. Blood, 127(5), 616–625. https://doi.org/10.1182/blood-2015-06-653113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., Saltness, A., & R., Jeganathan, K. B., Verzosa, G. C., Pezeshki, A., Khazaie, K., Miller, J. D., & van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530, 184. https://doi.org/10.1038/nature16932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., Chung, J. W., Kim, D. H., Poon, Y., David, N., Baker, D. J., van Deursen, J. M., Campisi, J., & Elisseeff, J. H. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature Medicine, 23(6), 775–781. https://doi.org/10.1038/nm.4324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Farr, J. N., Fraser, D. G., Wang, H., Jaehn, K., Ogrodnik, M. B., Weivoda, M. M., Drake, M. T., Tchkonia, T., LeBrasseur, N. K., Kirkland, J. L., Bonewald, L. F., Pignolo, R. J., Monroe, D. G., & Khosla, S. (2016). Identification of Senescent Cells in the Bone Microenvironment. Journal of Bone and Mineral Research, 31(11), 1920–1929. https://doi.org/10.1002/jbmr.2892

    Article  CAS  PubMed  Google Scholar 

  23. Lawrenson, K., Grun, B., Benjamin, E., Jacobs, I. J., Dafou, D., & Gayther, S. A. (2010). Senescent fibroblasts promote neoplastic transformation of partially transformed ovarian epithelial cells in a three-dimensional model of early stage ovarian cancer. Neoplasia, 12(4), 317–325. https://doi.org/10.1593/neo.91948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y., & Campisi, J. (2001). Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging. Proceedings of the National Academy of Sciences of the United States of America, 98(21), 12072–12077. https://doi.org/10.1073/pnas.211053698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Coppé, J. P., Patil, C. K., Rodier, F., Krtolica, A., Beauséjour, C. M., Parrinello, S., Hodgson, J. G., Chin, K., Desprez, P. Y., & Campisi, J. (2010). A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS ONE, 5(2), e9188. https://doi.org/10.1371/journal.pone.0009188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Di, G. H., Liu, Y., Lu, Y., Liu, J., Wu, C., & Duan, H. F. (2014). IL-6 secreted from senescent mesenchymal stem cells promotes proliferation and migration of breast cancer cells. PLoS ONE, 9(11), e113572. https://doi.org/10.1371/journal.pone.0113572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Laberge, R. M., Sun, Y., Orjalo, A. V., Patil, C. K., Freund, A., Zhou, L., Curran, S. C., Davalos, A. R., Wilson-Edell, K. A., Liu, S., Limbad, C., Demaria, M., Li, P., Hubbard, G. B., Ikeno, Y., Javors, M., Desprez, P. Y., Benz, C. C., Kapahi, P., Nelson, P. S., et al. (2015). MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nature Cell Biology, 17(8), 1049–1061. https://doi.org/10.1038/ncb3195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu, D., & Hornsby, P. J. (2007). Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Research, 67(7), 3117–3126. https://doi.org/10.1158/0008-5472.Can-06-3452

    Article  CAS  PubMed  Google Scholar 

  29. Luo, X., Fu, Y., Loza, A. J., Murali, B., Leahy, K. M., Ruhland, M. K., Gang, M., Su, X., Zamani, A., Shi, Y., Lavine, K. J., Ornitz, D. M., Weilbaecher, K. N., Long, F., Novack, D. V., Faccio, R., Longmore, G. D., & Stewart, S. A. (2016). Stromal-initiated changes in the bone promote metastatic niche development. Cell Reports, 14(1), 82–92. https://doi.org/10.1016/j.celrep.2015.12.016

    Article  CAS  PubMed  Google Scholar 

  30. Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, D., & Horwitz, E. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315–317. https://doi.org/10.1080/14653240600855905

    Article  CAS  PubMed  Google Scholar 

  31. Goulard, M., Dosquet, C., & Bonnet, D. (2018). Role of the microenvironment in myeloid malignancies. Cellular and Molecular Life Sciences, 75(8), 1377–1391. https://doi.org/10.1007/s00018-017-2725-4

    Article  CAS  PubMed  Google Scholar 

  32. Mendelson, A., & Frenette, P. S. (2014). Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nature Medicine, 20(8), 833–846. https://doi.org/10.1038/nm.3647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wei, Q., & Frenette, P. S. (2018). Niches for Hematopoietic Stem Cells and Their Progeny. Immunity, 48(4), 632–648. https://doi.org/10.1016/j.immuni.2018.03.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mitroulis, I., Kalafati, L., Bornhauser, M., Hajishengallis, G., & Chavakis, T. (2020). Regulation of the bone marrow niche by inflammation. Frontiers in Immunology, 11, 1540. https://doi.org/10.3389/fimmu.2020.01540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Passegue, E., Wagers, A. J., Giuriato, S., Anderson, W. C., & Weissman, I. L. (2005). Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. Journal of Experimental Medicine, 202(11), 1599–1611. https://doi.org/10.1084/jem.20050967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kunisaki, Y., Bruns, I., Scheiermann, C., Ahmed, J., Pinho, S., Zhang, D., Mizoguchi, T., Wei, Q., Lucas, D., Ito, K., Mar, J. C., Bergman, A., & Frenette, P. S. (2013). Arteriolar niches maintain haematopoietic stem cell quiescence. Nature, 502(7473), 637–643. https://doi.org/10.1038/nature12612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Acar, M., Kocherlakota, K. S., Murphy, M. M., Peyer, J. G., Oguro, H., Inra, C. N., Jaiyeola, C., Zhao, Z., Luby-Phelps, K., & Morrison, S. J. (2015). Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature, 526(7571), 126–130. https://doi.org/10.1038/nature15250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sugiyama, T., Kohara, H., Noda, M., & Nagasawa, T. (2006). Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity, 25(6), 977–988. https://doi.org/10.1016/j.immuni.2006.10.016

    Article  CAS  PubMed  Google Scholar 

  39. Omatsu, Y., Sugiyama, T., Kohara, H., Kondoh, G., Fujii, N., Kohno, K., & Nagasawa, T. (2010). The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity, 33(3), 387–399. https://doi.org/10.1016/j.immuni.2010.08.017

    Article  CAS  PubMed  Google Scholar 

  40. Mendez-Ferrer, S., Michurina, T. V., Ferraro, F., Mazloom, A. R., Macarthur, B. D., Lira, S. A., Scadden, D. T., Ma’ayan, A., Enikolopov, G. N., & Frenette, P. S. (2010). Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature, 466(7308), 829–834. https://doi.org/10.1038/nature09262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G., & Morrison, S. J. (2014). Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell, 15(2), 154–168. https://doi.org/10.1016/j.stem.2014.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lawson, M. A., McDonald, M. M., Kovacic, N., Hua Khoo, W., Terry, R. L., Down, J., Kaplan, W., Paton-Hough, J., Fellows, C., Pettitt, J. A., Neil Dear, T., Van Valckenborgh, E., Baldock, P. A., Rogers, M. J., Eaton, C. L., Vanderkerken, K., Pettit, A. R., Quinn, J. M., Zannettino, A. C., Phan, T. G., et al. (2015). Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nature Communications, 6, 8983. https://doi.org/10.1038/ncomms9983

    Article  CAS  PubMed  Google Scholar 

  43. Agarwal, P., & Bhatia, R. (2015). Influence of bone marrow microenvironment on leukemic stem cells: Breaking up an intimate relationship. Advances in Cancer Research, 127, 227–252. https://doi.org/10.1016/bs.acr.2015.04.007

    Article  CAS  PubMed  Google Scholar 

  44. Agarwal, P., Isringhausen, S., Li, H., Paterson, A. J., He, J., Gomariz, A., Nagasawa, T., Nombela-Arrieta, C., & Bhatia, R. (2019). Mesenchymal niche-specific expression of Cxcl12 controls quiescence of treatment-resistant leukemia stem cells. Cell Stem Cell, 24(5), 769–784 e766. https://doi.org/10.1016/j.stem.2019.02.018

  45. Kode, A., Manavalan, J. S., Mosialou, I., Bhagat, G., Rathinam, C. V., Luo, N., Khiabanian, H., Lee, A., Murty, V. V., Friedman, R., Brum, A., Park, D., Galili, N., Mukherjee, S., Teruya-Feldstein, J., Raza, A., Rabadan, R., Berman, E., & Kousteni, S. (2014). Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature, 506(7487), 240–244. https://doi.org/10.1038/nature12883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Krevvata, M., Silva, B. C., Manavalan, J. S., Galan-Diez, M., Kode, A., Matthews, B. G., Park, D., Zhang, C. A., Galili, N., Nickolas, T. L., Dempster, D. W., Dougall, W., Teruya-Feldstein, J., Economides, A. N., Kalajzic, I., Raza, A., Berman, E., Mukherjee, S., Bhagat, G., & Kousteni, S. (2014). Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood, 124(18), 2834–2846. https://doi.org/10.1182/blood-2013-07-517219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bowers, M., Zhang, B., Ho, Y., Agarwal, P., Chen, C. C., & Bhatia, R. (2015). Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development. Blood, 125(17), 2678–2688. https://doi.org/10.1182/blood-2014-06-582924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Raaijmakers, M. H., Mukherjee, S., Guo, S., Zhang, S., Kobayashi, T., Schoonmaker, J. A., Ebert, B. L., Al-Shahrour, F., Hasserjian, R. P., Scadden, E. O., Aung, Z., Matza, M., Merkenschlager, M., Lin, C., Rommens, J. M., & Scadden, D. T. (2010). Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature, 464(7290), 852–857. https://doi.org/10.1038/nature08851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Childs, B. G., Durik, M., Baker, D. J., & van Deursen, J. M. (2015). Cellular senescence in aging and age-related disease: From mechanisms to therapy. Nature Medicine, 21(12), 1424–1435. https://doi.org/10.1038/nm.4000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., Pereira-Smith, O., &, et al. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences of the United States of America, 92(20), 9363–9367. https://doi.org/10.1073/pnas.92.20.9363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mammoto, T., Torisawa, Y. S., Muyleart, M., Hendee, K., Anugwom, C., Gutterman, D., & Mammoto, A. (2019). Effects of age-dependent changes in cell size on endothelial cell proliferation and senescence through YAP1. Aging, 11(17), 7051–7069. https://doi.org/10.18632/aging.102236

  52. Kumari, R., & Jat, P. (2021). Mechanisms of cellular senescence: Cell cycle arrest and senescence associated secretory phenotype. Frontiers in Cell and Developmental Biology, 9, 645593. https://doi.org/10.3389/fcell.2021.645593

    Article  PubMed  PubMed Central  Google Scholar 

  53. Mirzayans, R., Andrais, B., Hansen, G., & Murray, D. (2012). Role of p16(INK4A) in Replicative Senescence and DNA Damage-induced premature senescence in p53-deficient human cells. Biochemistry Research International, 2012, 951574. https://doi.org/10.1155/2012/951574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Petrova, N. V., Velichko, A. K., Razin, S. V., & Kantidze, O. L. (2016). Small molecule compounds that induce cellular senescence. Aging Cell, 15(6), 999–1017. https://doi.org/10.1111/acel.12518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004). Ink4a/Arf expression is a biomarker of aging. Journal of Clinical Investigation, 114(9), 1299–1307. https://doi.org/10.1172/jci22475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Roninson, I. B. (2003). Tumor cell senescence in cancer treatment. Cancer Research, 63(11), 2705–2715.

    CAS  PubMed  Google Scholar 

  57. van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439–446. https://doi.org/10.1038/nature13193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang, E. (1995). Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Research, 55(11), 2284.

    CAS  PubMed  Google Scholar 

  59. Ray, D., & Yung, R. (2018). Immune senescence, epigenetics and autoimmunity. Clinical Immunology, 196, 59–63. https://doi.org/10.1016/j.clim.2018.04.002

    Article  CAS  PubMed  Google Scholar 

  60. Prata, L., Ovsyannikova, I. G., Tchkonia, T., & Kirkland, J. L. (2018). Senescent cell clearance by the immune system: Emerging therapeutic opportunities. Seminars in Immunology, 40, 101275. https://doi.org/10.1016/j.smim.2019.04.003

    Article  CAS  PubMed  Google Scholar 

  61. Coppe, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: The dark side of tumor suppression. Annual Review of Pathology, 5, 99–118. https://doi.org/10.1146/annurev-pathol-121808-102144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Freund, A., Orjalo, A. V., Desprez, P.-Y., & Campisi, J. (2010). Inflammatory networks during cellular senescence: Causes and consequences. Trends in Molecular Medicine, 16(5), 238–246. https://doi.org/10.1016/j.molmed.2010.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kale, A., Sharma, A., Stolzing, A., Desprez, P.-Y., & Campisi, J. (2020). Role of immune cells in the removal of deleterious senescent cells. Immunity & Ageing, 17(1), 16. https://doi.org/10.1186/s12979-020-00187-9

    Article  Google Scholar 

  64. Brennan, F. M., Maini, R. N., & Feldmann, M. (1995). Cytokine expression in chronic inflammatory disease. British Medical Bulletin, 51(2), 368–384. https://doi.org/10.1093/oxfordjournals.bmb.a072967

    Article  CAS  PubMed  Google Scholar 

  65. Caruso, C., Lio, D., Cavallone, L., & Franceschi, C. (2004). Aging, longevity, inflammation, and cancer. Annals of the New York Academy of Sciences, 1028, 1–13. https://doi.org/10.1196/annals.1322.001

    Article  CAS  PubMed  Google Scholar 

  66. Brod, S. A. (2000). Unregulated inflammation shortens human functional longevity. Inflammation Research, 49(11), 561–570. https://doi.org/10.1007/s000110050632

    Article  CAS  PubMed  Google Scholar 

  67. Buscarlet, M., Provost, S., Zada, Y. F., Barhdadi, A., Bourgoin, V., Lepine, G., Mollica, L., Szuber, N., Dube, M. P., & Busque, L. (2017). DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood, 130(6), 753–762. https://doi.org/10.1182/blood-2017-04-777029

    Article  CAS  PubMed  Google Scholar 

  68. Beerman, I., Bhattacharya, D., Zandi, S., Sigvardsson, M., Weissman, I. L., Bryder, D., & Rossi, D. J. (2010). Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proceedings of the National Academy of Sciences of the United States of America, 107(12), 5465–5470. https://doi.org/10.1073/pnas.1000834107

    Article  PubMed  PubMed Central  Google Scholar 

  69. Linton, P. J., & Dorshkind, K. (2004). Age-related changes in lymphocyte development and function. Nature Immunology, 5(2), 133–139. https://doi.org/10.1038/ni1033

    Article  CAS  PubMed  Google Scholar 

  70. Guralnik, J. M., Eisenstaedt, R. S., Ferrucci, L., Klein, H. G., & Woodman, R. C. (2004). Prevalence of anemia in persons 65 years and older in the United States: Evidence for a high rate of unexplained anemia. Blood, 104(8), 2263–2268. https://doi.org/10.1182/blood-2004-05-1812

    Article  CAS  PubMed  Google Scholar 

  71. Ogawa, T., Kitagawa, M., & Hirokawa, K. (2000). Age-related changes of human bone marrow: A histometric estimation of proliferative cells, apoptotic cells, T cells, B cells and macrophages. Mechanisms of Ageing and Development, 117(1–3), 57–68. https://doi.org/10.1016/s0047-6374(00)00137-8

    Article  CAS  PubMed  Google Scholar 

  72. Bousounis, P., Bergo, V., & Trompouki, E. (2021). Inflammation, aging and hematopoiesis: a complex relationship. Cells, 10(6), 1386. https://doi.org/10.3390/cells10061386

  73. Ergen, A. V., Boles, N. C., & Goodell, M. A. (2012). Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood, 119(11), 2500–2509. https://doi.org/10.1182/blood-2011-11-391730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhao, Y., Wu, D., Fei, C., Guo, J., Gu, S., Zhu, Y., Xu, F., Zhang, Z., Wu, L., Li, X., & Chang, C. (2015). Down-regulation of Dicer1 promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of mesenchymal stromal cells in patients with myelodysplastic syndrome. Haematologica, 100(2), 194–204. https://doi.org/10.3324/haematol.2014.109769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Guo, J., Zhao, Y., Fei, C., Zhao, S., Zheng, Q., Su, J., Wu, D., Li, X., & Chang, C. (2018). Dicer1 downregulation by multiple myeloma cells promotes the senescence and tumor-supporting capacity and decreases the differentiation potential of mesenchymal stem cells. Cell Death & Disease, 9(5), 512. https://doi.org/10.1038/s41419-018-0545-6

    Article  CAS  Google Scholar 

  76. Pang, W. W., Price, E. A., Sahoo, D., Beerman, I., Maloney, W. J., Rossi, D. J., Schrier, S. L., & Weissman, I. L. (2011). Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proceedings of the National Academy of Sciences of the United States of America, 108(50), 20012–20017. https://doi.org/10.1073/pnas.1116110108

    Article  PubMed  PubMed Central  Google Scholar 

  77. O’Hagan-Wong, K., Nadeau, S., Carrier-Leclerc, A., Apablaza, F., Hamdy, R., Shum-Tim, D., Rodier, F., & Colmegna, I. (2016). Increased IL-6 secretion by aged human mesenchymal stromal cells disrupts hematopoietic stem and progenitor cells’ homeostasis. Oncotarget, 7(12), 13285–13296. https://doi.org/10.18632/oncotarget.7690

    Article  PubMed  PubMed Central  Google Scholar 

  78. Adams, P. D., Jasper, H., & Rudolph, K. L. (2015). Aging-induced stem cell mutations as drivers for disease and cancer. Cell Stem Cell, 16, 601–612. https://doi.org/10.1016/j.stem.2015.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tsai, K. K., Chuang, E. Y., Little, J. B., & Yuan, Z. M. (2005). Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. Cancer Research, 65(15), 6734–6744. https://doi.org/10.1158/0008-5472.CAN-05-0703

    Article  CAS  PubMed  Google Scholar 

  80. Bavik, C., Coleman, I., Dean, J. P., Knudsen, B., Plymate, S., & Nelson, P. S. (2006). The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Research, 66(2), 794–802. https://doi.org/10.1158/0008-5472.CAN-05-1716

    Article  CAS  PubMed  Google Scholar 

  81. Takasugi, M., Okada, R., Takahashi, A., Virya Chen, D., Watanabe, S., & Hara, E. (2017). Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nature Communications, 8(1), 15729. https://doi.org/10.1038/ncomms15728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Li, Y., Xu, X., Wang, L., Liu, G., Li, Y., Wu, X., Jing, Y., Li, H., & Wang, G. (2015). Senescent mesenchymal stem cells promote colorectal cancer cells growth via galectin-3 expression. Cell & Bioscience, 5, 21. https://doi.org/10.1186/s13578-015-0012-3

    Article  CAS  Google Scholar 

  83. Capell, B. C., Drake, A. M., Zhu, J., Shah, P. P., Dou, Z., Dorsey, J., Simola, D. F., Donahue, G., Sammons, M., Rai, T. S., Natale, C., Ridky, T. W., Adams, P. D., & Berger, S. L. (2016). MLL1 is essential for the senescence-associated secretory phenotype. Genes and Development, 30(3), 321–336. https://doi.org/10.1101/gad.271882.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Coppe, J. P., Patil, C. K., Rodier, F., Sun, Y., Munoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P. Y., & Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology, 6(12), 2853–2868. https://doi.org/10.1371/journal.pbio.0060301

    Article  CAS  PubMed  Google Scholar 

  85. Krause, J. R. (2009). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues: An Overview. Critical Values, 2(2), 30–32. https://doi.org/10.1093/criticalvalues/2.2.30

    Article  Google Scholar 

  86. Geyh, S., Oz, S., Cadeddu, R. P., Frobel, J., Bruckner, B., Kundgen, A., Fenk, R., Bruns, I., Zilkens, C., Hermsen, D., Gattermann, N., Kobbe, G., Germing, U., Lyko, F., Haas, R., & Schroeder, T. (2013). Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia, 27(9), 1841–1851. https://doi.org/10.1038/leu.2013.193

    Article  CAS  PubMed  Google Scholar 

  87. Poloni, A., Maurizi, G., Mattiucci, D., Amatori, S., Fogliardi, B., Costantini, B., Mariani, M., Mancini, S., Olivieri, A., Fanelli, M., & Leoni, P. (2014). Overexpression of CDKN2B (p15INK4B) and altered global DNA methylation status in mesenchymal stem cells of high-risk myelodysplastic syndromes. Leukemia, 28(11), 2241–2244. https://doi.org/10.1038/leu.2014.197

    Article  CAS  PubMed  Google Scholar 

  88. Lopez-Villar, O., Garcia, J. L., Sanchez-Guijo, F. M., Robledo, C., Villaron, E. M., Hernández-Campo, P., Lopez-Holgado, N., Diez-Campelo, M., Barbado, M. V., Perez-Simon, J. A., Hernández-Rivas, J. M., San-Miguel, J. F., & del Cañizo, M. C. (2009). Both expanded and uncultured mesenchymal stem cells from MDS patients are genomically abnormal, showing a specific genetic profile for the 5q− syndrome. Leukemia, 23, 664. https://doi.org/10.1038/leu.2008.361

    Article  CAS  PubMed  Google Scholar 

  89. Aanei, C. M., Flandrin, P., Eloae, F. Z., Carasevici, E., Guyotat, D., Wattel, E., & Campos, L. (2012). Intrinsic growth deficiencies of mesenchymal stromal cells in myelodysplastic syndromes. Stem Cells and Development, 21(10), 1604–1615. https://doi.org/10.1089/scd.2011.0390

    Article  CAS  PubMed  Google Scholar 

  90. Fei, C., Zhao, Y., Guo, J., Gu, S., Li, X., & Chang, C. (2014). Senescence of bone marrow mesenchymal stromal cells is accompanied by activation of p53/p21 pathway in myelodysplastic syndromes. European Journal of Haematology, 93(6), 476–486. https://doi.org/10.1111/ejh.12385

    Article  CAS  PubMed  Google Scholar 

  91. Kornblau, S. M., Ruvolo, P. P., Wang, R. Y., Battula, V. L., Shpall, E. J., Ruvolo, V. R., McQueen, T., Qui, Y., Zeng, Z., Pierce, S., Jacamo, R., Yoo, S. Y., Le, P. M., Sun, J., Hail, N., Jr., Konopleva, M., & Andreeff, M. (2018). Distinct protein signatures of acute myeloid leukemia bone marrow-derived stromal cells are prognostic for patient survival. Haematologica, 103(5), 810–821. https://doi.org/10.3324/haematol.2017.172429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Chandran, P., Le, Y., Li, Y., Sabloff, M., Mehic, J., Rosu-Myles, M., & Allan, D. S. (2015). Mesenchymal stromal cells from patients with acute myeloid leukemia have altered capacity to expand differentiated hematopoietic progenitors. Leukemia Research, 39(4), 486–493. https://doi.org/10.1016/j.leukres.2015.01.013

    Article  CAS  PubMed  Google Scholar 

  93. Choi, H., Kim, Y., Kang, D., Kwon, A., Kim, J., Min Kim, J., Park, S. S., Kim, Y. J., Min, C. K., & Kim, M. (2020). Common and different alterations of bone marrow mesenchymal stromal cells in myelodysplastic syndrome and multiple myeloma. Cell Proliferation, 53(5), e12819. https://doi.org/10.1111/cpr.12819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Geyh, S., Rodríguez-Paredes, M., Jäger, P., Khandanpour, C., Cadeddu, R. P., Gutekunst, J., Wilk, C. M., Fenk, R., Zilkens, C., Hermsen, D., Germing, U., Kobbe, G., Lyko, F., Haas, R., & Schroeder, T. (2016). Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. Leukemia, 30(3), 683–691. https://doi.org/10.1038/leu.2015.325

    Article  CAS  PubMed  Google Scholar 

  95. Falconi, G., Fabiani, E., Fianchi, L., Criscuolo, M., Raffaelli, C. S., Bellesi, S., Hohaus, S., Voso, M. T., D'Alo, F., & Leone, G. (2016). Impairment of PI3K/AKT and WNT/beta-catenin pathways in bone marrow mesenchymal stem cells isolated from patients with myelodysplastic syndromes. Experimental Hematology, 44(1), 75–83 e71–74, https://doi.org/10.1016/j.exphem.2015.10.005

  96. Poon, Z., Dighe, N., Venkatesan, S. S., Cheung, A. M. S., Fan, X., Bari, S., Hota, M., Ghosh, S., & Hwang, W. Y. K. (2019). Bone marrow MSCs in MDS: Contribution towards dysfunctional hematopoiesis and potential targets for disease response to hypomethylating therapy. Leukemia, 33(6), 1487–1500. https://doi.org/10.1038/s41375-018-0310-y

    Article  PubMed  Google Scholar 

  97. Boada, M., Echarte, L., Guillermo, C., Diaz, L., Touriño, C., & Grille, S. (2021). 5-Azacytidine restores interleukin 6-increased production in mesenchymal stromal cells from myelodysplastic patients. Hematology, Transfusion and Cell Therapy, 43(1), 35–42. https://doi.org/10.1016/j.htct.2019.12.0

    Article  PubMed  Google Scholar 

  98. Lopes, M. R., Pereira, J. K., de Melo Campos, P., Machado-Neto, J. A., Traina, F., Saad, S. T., & Favaro, P. (2017). De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes. Scientific Reports, 7, 40707. https://doi.org/10.1038/srep40707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. von der Heide, E. K., Neumann, M., Vosberg, S., James, A. R., Schroeder, M. P., Ortiz-Tanchez, J., Isaakidis, K., Schlee, C., Luther, M., Johrens, K., Anagnostopoulos, I., Mochmann, L. H., Nowak, D., Hofmann, W. K., Greif, P. A., & Baldus, C. D. (2017). Molecular alterations in bone marrow mesenchymal stromal cells derived from acute myeloid leukemia patients. Leukemia, 31(5), 1069–1078. https://doi.org/10.1038/leu.2016.324

    Article  CAS  PubMed  Google Scholar 

  100. Cheng, J., Li, Y., Liu, S., Jiang, Y., Ma, J., Wan, L., Li, Q., & Pang, T. (2019). CXCL8 derived from mesenchymal stromal cells supports survival and proliferation of acute myeloid leukemia cells through the PI3K/AKT pathway. The Federation of American Societies of Experimental Biology Journal, 33(4), 4755–4764. https://doi.org/10.1096/fj.201801931R

    Article  CAS  Google Scholar 

  101. Pardanani, A., Finke, C., Lasho, T. L., Al-Kali, A., Begna, K. H., Hanson, C. A., & Tefferi, A. (2012). IPSS-independent prognostic value of plasma CXCL10, IL-7 and IL-6 levels in myelodysplastic syndromes. Leukemia, 26(4), 693–699. https://doi.org/10.1038/leu.2011.251

    Article  CAS  PubMed  Google Scholar 

  102. Shi, X., Zheng, Y., Xu, L., Cao, C., Dong, B., & Chen, X. (2019). The inflammatory cytokine profile of myelodysplastic syndromes: A meta-analysis. Medicine (Baltimore), 98(22), e15844. https://doi.org/10.1097/MD.0000000000015844

    Article  PubMed  Google Scholar 

  103. Desbourdes, L., Javary, J., Charbonnier, T., Ishac, N., Bourgeais, J., Iltis, A., Chomel, J. C., Turhan, A., Guilloton, F., Tarte, K., Demattei, M. V., Ducrocq, E., Rouleux-Bonnin, F., Gyan, E., Herault, O., & Domenech, J. (2017). Alteration analysis of bone marrow mesenchymal stromal cells from de novo acute myeloid leukemia patients at diagnosis. Stem Cells and Development, 26(10), 709–722. https://doi.org/10.1089/scd.2016.0295

    Article  CAS  PubMed  Google Scholar 

  104. Abdul-Aziz, A. M., Sun, Y., Hellmich, C., Marlein, C. R., Mistry, J., Forde, E., Piddock, R. E., Shafat, M. S., Morfakis, A., Mehta, T., Di Palma, F., Macaulay, I., Ingham, C. J., Haestier, A., Collins, A., Campisi, J., Bowles, K. M., & Rushworth, S. A. (2019). Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment. Blood, 133(5), 446–456. https://doi.org/10.1182/blood-2018-04-845420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Su, Y. C., Li, S. C., Wu, Y. C., Wang, L. M., Chao, K. S., & Liao, H. F. (2013). Resveratrol downregulates interleukin-6-stimulated sonic hedgehog signaling in human acute myeloid leukemia. Evidence-Based Complementary and Alternative Medicine, 2013, 547430. https://doi.org/10.1155/2013/547430

    Article  PubMed  PubMed Central  Google Scholar 

  106. Saily, M., Koistinen, P., Zheng, A., & Savolainen, E. R. (1998). Signaling through interleukin-6 receptor supports blast cell proliferation in acute myeloblastic leukemia. European Journal of Haematology, 61(3), 190–196. https://doi.org/10.1111/j.1600-0609.1998.tb01083.x

    Article  CAS  PubMed  Google Scholar 

  107. Abdul-Aziz, A. M., Shafat, M. S., Mehta, T. K., Di Palma, F., Lawes, M. J., Rushworth, S. A., & Bowles, K. M. (2017). MIF-Induced Stromal PKCbeta/IL8 Is Essential in Human Acute Myeloid Leukemia. Cancer Research, 77(2), 303–311. https://doi.org/10.1158/0008-5472.CAN-16-1095

    Article  CAS  PubMed  Google Scholar 

  108. Hallek, M., Cheson, B. D., Catovsky, D., Caligaris-Cappio, F., Dighiero, G., Dohner, H., Hillmen, P., Keating, M. J., Montserrat, E., Rai, K. R., Kipps, T. J., & International Workshop on Chronic Lymphocytic, L. (2008). Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: A report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood, 111(12), 5446–5456. https://doi.org/10.1182/blood-2007-06-093906

    Article  CAS  Google Scholar 

  109. Pontikoglou, C., Kastrinaki, M. C., Klaus, M., Kalpadakis, C., Katonis, P., Alpantaki, K., Pangalis, G. A., & Papadaki, H. A. (2013). Study of the quantitative, functional, cytogenetic, and immunoregulatory properties of bone marrow mesenchymal stem cells in patients with B-cell chronic lymphocytic leukemia. Stem Cells and Development, 22(9), 1329–1341. https://doi.org/10.1089/scd.2012.0255

    Article  CAS  PubMed  Google Scholar 

  110. Janel, A., Dubois-Galopin, F., Bourgne, C., Berger, J., Tarte, K., Boiret-Dupre, N., Boisgard, S., Verrelle, P., Dechelotte, P., Tournilhac, O., & Berger, M. G. (2014). The chronic lymphocytic leukemia clone disrupts the bone marrow microenvironment. Stem Cells and Development, 23(24), 2972–2982. https://doi.org/10.1089/scd.2014.0229

    Article  CAS  PubMed  Google Scholar 

  111. Kay, N. E., Shanafelt, T. D., Strege, A. K., Lee, Y. K., Bone, N. D., & Raza, A. (2007). Bone biopsy derived marrow stromal elements rescue chronic lymphocytic leukemia B-cells from spontaneous and drug induced cell death and facilitates an “angiogenic switch.” Leukemia Research, 31(7), 899–906. https://doi.org/10.1016/j.leukres.2006.11.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Fayad, L., Keating, M. J., Reuben, J. M., O’Brien, S., Lee, B. N., Lerner, S., & Kurzrock, R. (2001). Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: Correlation with phenotypic characteristics and outcome. Blood, 97(1), 256–263. https://doi.org/10.1182/blood.v97.1.256

    Article  CAS  PubMed  Google Scholar 

  113. Molica, S., Vitelli, G., Levato, D., Gandolfo, G. M., & Liso, V. (1999). Increased serum levels of vascular endothelial growth factor predict risk of progression in early B-cell chronic lymphocytic leukaemia. British Journal of Haematology, 107(3), 605–610. https://doi.org/10.1046/j.1365-2141.1999.01752.x

    Article  CAS  PubMed  Google Scholar 

  114. Wierda, W. G., Johnson, M. M., Do, K. A., Manshouri, T., Dey, A., O’Brien, S., Giles, F. J., Kantarjian, H., Thomas, D., Faderl, S., Lerner, S., Keating, M., & Albitar, M. (2003). Plasma interleukin 8 level predicts for survival in chronic lymphocytic leukaemia. British Journal of Haematology, 120(3), 452–456. https://doi.org/10.1046/j.1365-2141.2003.04118.x

    Article  PubMed  Google Scholar 

  115. Yoon, J. Y., Lafarge, S., Dawe, D., Lakhi, S., Kumar, R., Morales, C., Marshall, A., Gibson, S. B., & Johnston, J. B. (2012). Association of interleukin-6 and interleukin-8 with poor prognosis in elderly patients with chronic lymphocytic leukemia. Leukemia and Lymphoma, 53(9), 1735–1742. https://doi.org/10.3109/10428194.2012.666662

    Article  CAS  PubMed  Google Scholar 

  116. Lai, R., O’Brien, S., Maushouri, T., Rogers, A., Kantarjian, H., Keating, M., & Albitar, M. (2002). Prognostic value of plasma interleukin-6 levels in patients with chronic lymphocytic leukemia. Cancer, 95(5), 1071–1075. https://doi.org/10.1002/cncr.10772

    Article  CAS  PubMed  Google Scholar 

  117. Ferrajoli, A., Keating, M. J., Manshouri, T., Giles, F. J., Dey, A., Estrov, Z., Koller, C. A., Kurzrock, R., Thomas, D. A., Faderl, S., Lerner, S., O’Brien, S., & Albitar, M. (2002). The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia. Blood, 100(4), 1215–1219. https://doi.org/10.1182/blood.V100.4.1215.h81602001215_1215_1219

    Article  CAS  PubMed  Google Scholar 

  118. Zhu, F., McCaw, L., Spaner, D. E., & Gorczynski, R. M. (2018). Targeting the IL-17/IL-6 axis can alter growth of chronic lymphocytic leukemia in vivo/in vitro. Leukemia Research, 66, 28–38. https://doi.org/10.1016/j.leukres.2018.01.006

    Article  CAS  PubMed  Google Scholar 

  119. Panayiotidis, P., Jones, D., Ganeshaguru, K., Foroni, L., & Hoffbrand, A. V. (1996). Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro. British Journal of Haematology, 92(1), 97–103. https://doi.org/10.1046/j.1365-2141.1996.00305.x

    Article  CAS  PubMed  Google Scholar 

  120. Trimarco, V., Ave, E., Facco, M., Chiodin, G., Frezzato, F., Martini, V., Gattazzo, C., Lessi, F., Giorgi, C. A., Visentin, A., Castelli, M., Severin, F., Zambello, R., Piazza, F., Semenzato, G., & Trentin, L. (2015). Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival. Oncotarget, 6(39), 42130–42149. https://doi.org/10.18632/oncotarget.6239

    Article  PubMed  PubMed Central  Google Scholar 

  121. Crompot, E., Van Damme, M., Pieters, K., Vermeersch, M., Perez-Morga, D., Mineur, P., Maerevoet, M., Meuleman, N., Bron, D., Lagneaux, L., & Stamatopoulos, B. (2017). Extracellular vesicles of bone marrow stromal cells rescue chronic lymphocytic leukemia B cells from apoptosis, enhance their migration and induce gene expression modifications. Haematologica, 102(9), 1594–1604. https://doi.org/10.3324/haematol.2016.163337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gehrke, I., Gandhirajan, R. K., Poll-Wolbeck, S. J., Hallek, M., & Kreuzer, K. A. (2011). Bone marrow stromal cell-derived vascular endothelial growth factor (VEGF) rather than chronic lymphocytic leukemia (CLL) cell-derived VEGF is essential for the apoptotic resistance of cultured CLL cells. Molecular Medicine, 17(7–8), 619–627. https://doi.org/10.2119/molmed.2010.00210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lee, Y. K., Bone, N. D., Strege, A. K., Shanafelt, T. D., Jelinek, D. F., & Kay, N. E. (2004). VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG). B-cell chronic lymphocytic leukemia. Blood, 104(3), 788–794. https://doi.org/10.1182/blood-2003-08-2763

    Article  CAS  PubMed  Google Scholar 

  124. Paesler, J., Gehrke, I., Gandhirajan, R. K., Filipovich, A., Hertweck, M., Erdfelder, F., Uhrmacher, S., Poll-Wolbeck, S. J., Hallek, M., & Kreuzer, K. A. (2010). The vascular endothelial growth factor receptor tyrosine kinase inhibitors vatalanib and pazopanib potently induce apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo. Clinical Cancer Research, 16(13), 3390–3398. https://doi.org/10.1158/1078-0432.CCR-10-0232

    Article  CAS  PubMed  Google Scholar 

  125. Francia di Celle, P., Mariani, S., Riera, L., Stacchini, A., Reato, G., & Foa, R. (1996). Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion. Blood, 87(10), 4382–4389. https://doi.org/10.1182/blood.V87.10.4382.bloodjournal87104382

    Article  CAS  PubMed  Google Scholar 

  126. Blanco, G., Puiggros, A., Sherry, B., Nonell, L., Calvo, X., Puigdecanet, E., Chiu, P. Y., Kieso, Y., Ferrer, G., Palacios, F., Arnal, M., Rodriguez-Rivera, M., Gimeno, E., Abella, E., Rai, K. R., Abrisqueta, P., Bosch, F., Calon, A., Ferrer, A., Chiorazzi, N., et al. (2021). Chronic lymphocytic leukemia-like monoclonal B-cell lymphocytosis exhibits an increased inflammatory signature that is reduced in early-stage chronic lymphocytic leukemia. Experimental Hematology, 95, 68–80. https://doi.org/10.1016/j.exphem.2020.12.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Aguilar-Santelises, M., Loftenius, A., Ljungh, C., Svenson, S. B., Andersson, B., Mellstedt, H., & Jondal, M. (1992). Serum levels of helper factors (IL-1α, IL-1β and IL-6), T-cell products (sCD4 and sCD8), sIL-2R and β2-microglobulin in patients with B-CLL and benign B lymphocytosis. Leukemia Research, 16(6–7), 607–613. https://doi.org/10.1016/0145-2126(92)90009-v

    Article  CAS  PubMed  Google Scholar 

  128. Rajkumar, S. V., Dimopoulos, M. A., Palumbo, A., Blade, J., Merlini, G., Mateos, M. V., Kumar, S., Hillengass, J., Kastritis, E., Richardson, P., Landgren, O., Paiva, B., Dispenzieri, A., Weiss, B., LeLeu, X., Zweegman, S., Lonial, S., Rosinol, L., Zamagni, E., Jagannath, S., et al. (2014). International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncology, 15(12), e538-548. https://doi.org/10.1016/S1470-2045(14)70442-5

    Article  PubMed  Google Scholar 

  129. Andre, T., Meuleman, N., Stamatopoulos, B., De Bruyn, C., Pieters, K., Bron, D., & Lagneaux, L. (2013). Evidences of early senescence in multiple myeloma bone marrow mesenchymal stromal cells. PLoS ONE, 8(3), e59756. https://doi.org/10.1371/journal.pone.0059756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Garderet, L., Mazurier, C., Chapel, A., Ernou, I., Boutin, L., Holy, X., Gorin, N. C., Lopez, M., Doucet, C., & Lataillade, J. J. (2007). Mesenchymal stem cell abnormalities in patients with multiple myeloma. Leukemia Lymphoma, 48(10), 2032–2041. https://doi.org/10.1080/10428190701593644

    Article  CAS  PubMed  Google Scholar 

  131. Xu, S., Evans, H., Buckle, C., De Veirman, K., Hu, J., Xu, D., Menu, E., De Becker, A., Vande Broek, I., Leleu, X., Camp, B. V., Croucher, P., Vanderkerken, K., & Van Riet, I. (2012). Impaired osteogenic differentiation of mesenchymal stem cells derived from multiple myeloma patients is associated with a blockade in the deactivation of the Notch signaling pathway. Leukemia, 26(12), 2546–2549. https://doi.org/10.1038/leu.2012.126

    Article  CAS  PubMed  Google Scholar 

  132. Corre, J., Mahtouk, K., Attal, M., Gadelorge, M., Huynh, A., Fleury-Cappellesso, S., Danho, C., Laharrague, P., Klein, B., Reme, T., & Bourin, P. (2007). Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia, 21(5), 1079–1088. https://doi.org/10.1038/sj.leu.2404621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Guo, J., Fei, C., Zhao, Y., Zhao, S., Zheng, Q., Su, J., Wu, D., Li, X., & Chang, C. (2017). Lenalidomide restores the osteogenic differentiation of bone marrow mesenchymal stem cells from multiple myeloma patients via deactivating Notch signaling pathway. Oncotarget, 8(33), 55405–55421. https://doi.org/10.18632/oncotarget.19265

    Article  PubMed  PubMed Central  Google Scholar 

  134. Mehdi, S. J., Johnson, S. K., Epstein, J., Zangari, M., Qu, P., Hoering, A., van Rhee, F., Schinke, C., Thanendrarajan, S., Barlogie, B., Davies, F. E., Morgan, G. J., & Yaccoby, S. (2019). Mesenchymal stem cells gene signature in high-risk myeloma bone marrow linked to suppression of distinct IGFBP2-expressing small adipocytes. British Journal of Haematology, 184(4), 578–593. https://doi.org/10.1111/bjh.15669

    Article  CAS  PubMed  Google Scholar 

  135. Berenstein, R., Blau, O., Nogai, A., Waechter, M., Slonova, E., Schmidt-Hieber, M., Kunitz, A., Pezzutto, A., Doerken, B., & Blau, I. W. (2015). Multiple myeloma cells alter the senescence phenotype of bone marrow mesenchymal stromal cells under participation of the DLK1-DIO3 genomic region. BMC Cancer, 15(1), 68. https://doi.org/10.1186/s12885-015-1078-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Fairfield, H., Costa, S., Falank, C., Farrell, M., Murphy, C. S., D’Amico, A., Driscoll, H., & Reagan, M. R. (2020). Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes. Frontiers in Oncology, 10, 584683. https://doi.org/10.3389/fonc.2020.584683

    Article  PubMed  Google Scholar 

  137. Mahtouk, K., Moreaux, J., Hose, D., Reme, T., Meissner, T., Jourdan, M., Rossi, J. F., Pals, S. T., Goldschmidt, H., & Klein, B. (2010). Growth factors in multiple myeloma: A comprehensive analysis of their expression in tumor cells and bone marrow environment using Affymetrix microarrays. BMC Cancer, 10(1), 198. https://doi.org/10.1186/1471-2407-10-198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wallace, S. R., Oken, M. M., Lunetta, K. L., Panoskaltsis-Mortari, A., & Masellis, A. M. (2001). Abnormalities of bone marrow mesenchymal cells in multiple myeloma patients. Cancer, 91(7), 1219–1230. https://doi.org/10.1002/1097-0142(20010401)91:7%3c1219::aid-cncr1122%3e3.0.co;2-1

    Article  CAS  PubMed  Google Scholar 

  139. Arnulf, B., Lecourt, S., Soulier, J., Ternaux, B., Lacassagne, M. N., Crinquette, A., Dessoly, J., Sciaini, A. K., Benbunan, M., Chomienne, C., Fermand, J. P., Marolleau, J. P., & Larghero, J. (2007). Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma. Leukemia, 21(1), 158–163. https://doi.org/10.1038/sj.leu.2404466

    Article  CAS  PubMed  Google Scholar 

  140. Tanno, T., Lim, Y., Wang, Q., Chesi, M., Bergsagel, P. L., Matthews, G., Johnstone, R. W., Ghosh, N., Borrello, I., Huff, C. A., & Matsui, W. (2014). Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells. Blood, 123(5), 725–733. https://doi.org/10.1182/blood-2013-08-524025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Bataille, R., Jourdan, M., Zhang, X. G., & Klein, B. (1989). Serum levels of interleukin 6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias. Journal of Clinical Investigation, 84(6), 2008–2011. https://doi.org/10.1172/JCI114392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ludwig, H., Nachbaur, D. M., Fritz, E., Krainer, M., & Huber, H. (1991). Interleukin-6 is a prognostic factor in multiple myeloma. Blood, 77(12), 2794–2795. https://doi.org/10.1182/blood.V77.12.2794.2794

    Article  CAS  PubMed  Google Scholar 

  143. Pelliniemi, T. T., Irjala, K., Mattila, K., Pulkki, K., Rajamaki, A., Tienhaara, A., Laakso, M., & Lahtinen, R. (1995). Immunoreactive interleukin-6 and acute phase proteins as prognostic factors in multiple myeloma. Blood, 85(3), 765–771. https://doi.org/10.1182/blood.V85.3.765.bloodjournal853765

    Article  CAS  PubMed  Google Scholar 

  144. Thaler, J., Fechner, F., Herold, M., & Huber, H. (1994). Interleukin-6 in multiple myeloma: Correlation with disease activity and Ki-67 proliferation index. Leukemia & Lymphoma, 12(3–4), 265–271. https://doi.org/10.3109/10428199409059598

    Article  CAS  Google Scholar 

  145. Banaszkiewicz, M., Malyszko, J., Batko, K., Koc-Zorawska, E., Zorawski, M., Dumnicka, P., Jurczyszyn, A., Woziwodzka, K., Tisonczyk, J., Krzanowski, M., Malyszko, J., Waszczuk-Gajda, A., Drozdz, R., Kuzniewski, M., & Krzanowska, K. (2020). Evaluating the relationship of GDF-15 with clinical characteristics, cardinal features, and survival in multiple myeloma. Mediators of Inflammation, 5657864. https://doi.org/10.1155/2020/5657864

  146. Alexandrakis, M. G., Passam, F. H., Boula, A., Christophoridou, A., Aloizos, G., Roussou, P., & Kyriakou, D. S. (2003). Relationship between circulating serum soluble interleukin-6 receptor and the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in multiple myeloma. Annals of Hematology, 82(1), 19–23. https://doi.org/10.1007/s00277-002-0558-0

    Article  CAS  PubMed  Google Scholar 

  147. Corre, J., Labat, E., Espagnolle, N., Hebraud, B., Avet-Loiseau, H., Roussel, M., Huynh, A., Gadelorge, M., Cordelier, P., Klein, B., Moreau, P., Facon, T., Fournie, J. J., Attal, M., & Bourin, P. (2012). Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma. Cancer Research, 72(6), 1395–1406. https://doi.org/10.1158/0008-5472.CAN-11-0188

    Article  CAS  PubMed  Google Scholar 

  148. Tarkun, P., Birtas Atesoglu, E., Mehtap, O., Musul, M. M., & Hacihanefioglu, A. (2014). Serum growth differentiation factor 15 levels in newly diagnosed multiple myeloma patients. Acta Haematologica, 131(3), 173–178. https://doi.org/10.1159/000354835

    Article  CAS  PubMed  Google Scholar 

  149. Mei, S., Wang, H., Fu, R., Qu, W., Xing, L., Wang, G., Song, J., Liu, H., Li, L., Wang, X., Wu, Y., Guan, J., Ruan, E., & Shao, Z. (2014). Hepcidin and GDF15 in anemia of multiple myeloma. International Journal of Hematology, 100(3), 266–273. https://doi.org/10.1007/s12185-014-1626-7

    Article  CAS  PubMed  Google Scholar 

  150. Zingone, A., Wang, W., Corrigan-Cummins, M., Wu, S. P., Plyler, R., Korde, N., Kwok, M., Manasanch, E. E., Tageja, N., Bhutani, M., Mulquin, M., Zuchlinski, D., Yancey, M. A., Roschewski, M., Zhang, Y., Roccaro, A. M., Ghobrial, I. M., Calvo, K. R., & Landgren, O. (2014). Altered cytokine and chemokine profiles in multiple myeloma and its precursor disease. Cytokine, 69(2), 294–297. https://doi.org/10.1016/j.cyto.2014.05.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Stasi, R., Brunetti, M., Parma, A., Di Giulio, C., Terzoli, E., & Pagano, A. (1998). The prognostic value of soluble interleukin-6 receptor in patients with multiple myeloma. Cancer, 82(10), 1860–1866. https://doi.org/10.1002/(SICI)1097-0142(19980515)82:10%3c1860::AID-CNCR7%3e3.0.CO;2-R

    Article  CAS  PubMed  Google Scholar 

  152. Uchiyama, H., Barut, B. A., Mohrbacher, A. F., Chauhan, D., & Anderson, K. C. (1993). Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood, 82(12), 3712–3720. https://doi.org/10.1182/blood.V82.12.3712.3712

    Article  CAS  PubMed  Google Scholar 

  153. Attar-Schneider, O., Zismanov, V., Dabbah, M., Tartakover-Matalon, S., Drucker, L., & Lishner, M. (2016). Multiple myeloma and bone marrow mesenchymal stem cells’ crosstalk: Effect on translation initiation. Molecular Carcinogenesis, 55(9), 1343–1354. https://doi.org/10.1002/mc.22378

    Article  CAS  PubMed  Google Scholar 

  154. Roccaro, A. M., Sacco, A., Maiso, P., Azab, A. K., Tai, Y. T., Reagan, M., Azab, F., Flores, L. M., Campigotto, F., Weller, E., Anderson, K. C., Scadden, D. T., & Ghobrial, I. M. (2013). BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. Journal of Clinical Investigation, 123(4), 1542–1555. https://doi.org/10.1172/JCI66517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Kanehira, M., Fujiwara, T., Nakajima, S., Okitsu, Y., Onishi, Y., Fukuhara, N., Ichinohasama, R., Okada, Y., & Harigae, H. (2017). An lysophosphatidic acid receptors 1 and 3 axis governs cellular senescence of mesenchymal stromal cells and promotes growth and vascularization of multiple myeloma. Stem Cells, 35(3), 739–753. https://doi.org/10.1002/stem.2499

    Article  CAS  PubMed  Google Scholar 

  156. Urashima, M., Ogata, A., Chauhan, D., Vidriales, M., Teoh, G., Hoshi, Y., Schlossman, R., DeCaprio, J., & Anderson, K. (1996). Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein. Blood, 88(6), 2219–2227. https://doi.org/10.1182/blood.V88.6.2219.bloodjournal8862219

    Article  CAS  PubMed  Google Scholar 

  157. Lokhorst, H. M., Lamme, T., de Smet, M., Klein, S., de Weger, R. A., van Oers, R., & Bloem, A. C. (1994). Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures. Blood, 84(7), 2269–2277. https://doi.org/10.1182/blood.V84.7.2269.2269

    Article  CAS  PubMed  Google Scholar 

  158. Klein, B., Zhang, X. G., Jourdan, M., Content, J., Houssiau, F., Aarden, L., Piechaczyk, M., & Bataille, R. (1989). Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood, 73(2), 517–526. https://doi.org/10.1182/blood.V73.2.517.517

    Article  CAS  PubMed  Google Scholar 

  159. Zhang, X. G., Klein, B., & Bataille, R. (1989). Interleukin-6 is a potent myeloma-cell growth factor in patients with aggressive multiple myeloma. Blood, 74(1), 11–13. https://doi.org/10.1182/blood.V74.1.11.11

    Article  CAS  PubMed  Google Scholar 

  160. Fulciniti, M., Hideshima, T., Vermot-Desroches, C., Pozzi, S., Nanjappa, P., Shen, Z., Patel, N., Smith, E. S., Wang, W., Prabhala, R., Tai, Y. T., Tassone, P., Anderson, K. C., & Munshi, N. C. (2009). A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clinical Cancer Research, 15(23), 7144–7152. https://doi.org/10.1158/1078-0432.CCR-09-1483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Teoh, H. K., Chong, P. P., Abdullah, M., Sekawi, Z., Tan, G. C., Leong, C. F., & Cheong, S. K. (2016). Small interfering RNA silencing of interleukin-6 in mesenchymal stromal cells inhibits multiple myeloma cell growth. Leukemia Research, 40, 44–53. https://doi.org/10.1016/j.leukres.2015.10.004

    Article  CAS  PubMed  Google Scholar 

  162. Rossi, J. F., Fegueux, N., Lu, Z. Y., Legouffe, E., Exbrayat, C., Bozonnat, M. C., Navarro, R., Lopez, E., Quittet, P., Daures, J. P., Rouille, V., Kanouni, T., Widjenes, J., & Klein, B. (2005). Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: Results of a pilot study including biological aspects. Bone Marrow Transplantation, 36(9), 771–779. https://doi.org/10.1038/sj.bmt.1705138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Moreau, P., Harousseau, J. L., Wijdenes, J., Morineau, N., Milpied, N., & Bataille, R. (2000). A combination of anti-interleukin 6 murine monoclonal antibody with dexamethasone and high-dose melphalan induces high complete response rates in advanced multiple myeloma. British Journal of Haematology, 109(3), 661–664. https://doi.org/10.1046/j.1365-2141.2000.02093.x

    Article  CAS  PubMed  Google Scholar 

  164. Voorhees, P. M., Manges, R. F., Sonneveld, P., Jagannath, S., Somlo, G., Krishnan, A., Lentzsch, S., Frank, R. C., Zweegman, S., Wijermans, P. W., Orlowski, R. Z., Kranenburg, B., Hall, B., Casneuf, T., Qin, X., van de Velde, H., Xie, H., & Thomas, S. K. (2013). A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. British Journal of Haematology, 161(3), 357–366. https://doi.org/10.1111/bjh.12266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Brighton, T. A., Khot, A., Harrison, S. J., Ghez, D., Weiss, B. M., Kirsch, A., Magen, H., Gironella, M., Oriol, A., Streetly, M., Kranenburg, B., Qin, X., Bandekar, R., Hu, P., Guilfoyle, M., Qi, M., Nemat, S., & Goldschmidt, H. (2019). Randomized, double-blind, placebo-controlled, multicenter study of siltuximab in high-risk smoldering multiple myeloma. Clinical Cancer Research, 25(13), 3772–3775. https://doi.org/10.1158/1078-0432.CCR-18-3470

    Article  CAS  PubMed  Google Scholar 

  166. Jourdan, M., Tarte, K., Legouffe, E., Brochier, J., Rossi, J. F., & Klein, B. (1999). Tumor necrosis factor is a survival and proliferation factor for human myeloma cells. European Cytokine Network, 10(1), 65–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Bosseboeuf, A., Allain-Maillet, S., Mennesson, N., Tallet, A., Rossi, C., Garderet, L., Caillot, D., Moreau, P., Piver, E., Girodon, F., Perreault, H., Brouard, S., Nicot, A., Bigot-Corbel, E., Hermouet, S., & Harb, J. (2017). Pro-inflammatory state in monoclonal gammopathy of undetermined significance and in multiple myeloma is characterized by low sialylation of pathogen-specific and other monoclonal immunoglobulins. Frontiers in Immunology, 8, 1347. https://doi.org/10.3389/fimmu.2017.01347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Tsirakis, G., Pappa, C. A., Spanoudakis, M., Chochlakis, D., Alegakis, A., Psarakis, F. E., Stratinaki, M., Stathopoulos, E. N., & Alexandrakis, M. G. (2012). Clinical significance of sCD105 in angiogenesis and disease activity in multiple myeloma. European Journal of Internal Medicine, 23(4), 368–373. https://doi.org/10.1016/j.ejim.2012.01.012

    Article  CAS  PubMed  Google Scholar 

  169. Schneiderova, P., Pika, T., Gajdos, P., Fillerova, R., Kromer, P., Kudelka, M., Minarik, J., Papajik, T., Scudla, V., & Kriegova, E. (2017). Serum protein fingerprinting by PEA immunoassay coupled with a pattern-recognition algorithms distinguishes MGUS and multiple myeloma. Oncotarget, 8(41), 69408–69421. https://doi.org/10.18632/oncotarget.11242

    Article  PubMed  Google Scholar 

  170. Merico, F., Bergui, L., Gregoretti, M. G., Ghia, P., Aimo, G., Lindley, I. J., & Caligaris-Cappio, F. (1993). Cytokines involved in the progression of multiple myeloma. Clinical Experimental Immunology, 92(1), 27–31. https://doi.org/10.1111/j.1365-2249.1993.tb05943.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Tarantini, S., Balasubramanian, P., Delfavero, J., Csipo, T., Yabluchanskiy, A., Kiss, T., Nyul-Toth, A., Mukli, P., Toth, P., Ahire, C., Ungvari, A., Benyo, Z., Csiszar, A., & Ungvari, Z. (2021). Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice. Geroscience, 43(5), 2427–2440. https://doi.org/10.1007/s11357-021-00440-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Pan, J., Li, D., Xu, Y., Zhang, J., Wang, Y., Chen, M., Lin, S., Huang, L., Chung, E. J., Citrin, D. E., Wang, Y., Hauer-Jensen, M., Zhou, D., & Meng, A. (2017). Inhibition of Bcl-2/xl with ABT-263 selectively kills senescent type II pneumocytes and reverses persistent pulmonary fibrosis induced by ionizing radiation in mice. International Journal of Radiation Oncology Biology Physics, 99(2), 353–361. https://doi.org/10.1016/j.ijrobp.2017.02.216

    Article  CAS  PubMed  Google Scholar 

  173. Chang, J., Wang, Y., Shao, L., Laberge, R.-M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N. E., Ding, S., Feng, W., Luo, Y., Wang, X., Aykin-Burns, N., Krager, K., Ponnappan, U., Hauer-Jensen, M., Meng, A., & Zhou, D. (2016). Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature Medicine, 22(1), 78–83. https://doi.org/10.1038/nm.4010

    Article  CAS  PubMed  Google Scholar 

  174. Kim, H. N., Chang, J., Shao, L., Han, L., Iyer, S., Manolagas, S. C., O’Brien, C. A., Jilka, R. L., Zhou, D., & Almeida, M. (2017). DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age. Aging Cell, 16(4), 693–703. https://doi.org/10.1111/acel.12597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Sharma, A. K., Roberts, R. L., Benson, R. D., Jr., Pierce, J. L., Yu, K., Hamrick, M. W., & McGee-Lawrence, M. E. (2020). The senolytic drug navitoclax (ABT-263) causes trabecular bone loss and impaired osteoprogenitor function in aged mice. Frontiers in Cell and Developmental Biology, 8(354). https://doi.org/10.3389/fcell.2020.00354

  176. Grezella, C., Fernandez-Rebollo, E., Franzen, J., Ventura Ferreira, M. S., Beier, F., & Wagner, W. (2018). Effects of senolytic drugs on human mesenchymal stromal cells. Stem Cell Research & Therapy, 9(1), 108. https://doi.org/10.1186/s13287-018-0857-6

    Article  CAS  Google Scholar 

  177. Song, X., Dai, J., Li, H., Li, Y., Hao, W., Zhang, Y., Zhang, Y., Su, L., & Wei, H. (2019). Anti-aging effects exerted by Tetramethylpyrazine enhances self-renewal and neuronal differentiation of rat bMSCs by suppressing NF-kB signaling. Bioscience Reports, 39(6). https://doi.org/10.1042/BSR20190761

  178. Gao, B., Lin, X., Jing, H., Fan, J., Ji, C., Jie, Q., Zheng, C., Wang, D., Xu, X., Hu, Y., Lu, W., Luo, Z., & Yang, L. (2018). Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti-inflammatory and angiogenic environment in aging mice. Aging Cell, 17(3), e12741. https://doi.org/10.1111/acel.12741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., O’Hara, S. P., LaRusso, N. F., Miller, J. D., Roos, C. M., Verzosa, G. C., LeBrasseur, N. K., Wren, J. D., Farr, J. N., Khosla, S., Stout, M. B., et al. (2015). The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell, 14(4), 644–658. https://doi.org/10.1111/acel.12344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Farr, J. N., Xu, M., Weivoda, M. M., Monroe, D. G., Fraser, D. G., Onken, J. L., Negley, B. A., Sfeir, J. G., Ogrodnik, M. B., Hachfeld, C. M., LeBrasseur, N. K., Drake, M. T., Pignolo, R. J., Pirtskhalava, T., Tchkonia, T., Oursler, M. J., Kirkland, J. L., & Khosla, S. (2017). Targeting cellular senescence prevents age-related bone loss in mice. Nature Medicine, 23(9), 1072–1079. https://doi.org/10.1038/nm.4385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Hickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., Kellogg, T. A., Khosla, S., Koerber, D. M., Lagnado, A. B., Lawson, D. K., LeBrasseur, N. K., Lerman, L. O., McDonald, K. M., McKenzie, T. J., Passos, J. F., et al. (2019). Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. eBioMedicine, 47, 446–456. https://doi.org/10.1016/j.ebiom.2019.08.069

    Article  PubMed  PubMed Central  Google Scholar 

  182. Justice, J. N., Nambiar, A. M., Tchkonia, T., LeBrasseur, N. K., Pascual, R., Hashmi, S. K., Prata, L., Masternak, M. M., Kritchevsky, S. B., Musi, N., & Kirkland, J. L. (2019). Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. eBioMedicine, 40, 554–563. https://doi.org/10.1016/j.ebiom.2018.12.052

    Article  PubMed  PubMed Central  Google Scholar 

  183. Thaler, J., Fechner, F., Herold, M., & Huber, H. (1994). Interleukin-6 in multiple myeloma: Correlation with disease activity and Ki-67 proliferation index. Leukaemia & Lymphoma, 12(3–4), 265–271. https://doi.org/10.3109/10428199409059598

    Article  CAS  Google Scholar 

  184. Banaszkiewicz, M., Malyszko, J., Batko, K., Koc-Zorawska, E., Zorawski, M., Dumnicka, P., Jurczyszyn, A., Woziwodzka, K., Tisonczyk, J., Krzanowski, M., Malyszko, J., Waszczuk-Gajda, A., Drozdz, R., Kuzniewski, M., & Krzanowska, K. (2020). Evaluating the relationship of GDF-15 with clinical characteristics, cardinal features, and survival in multiple myeloma. Mediators of Inflammation, 2020, 5657864. https://doi.org/10.1155/2020/5657864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Bonilla, X., Vanegas, N. P., & Vernot, J. P. (2019). Acute leukemia induces senescence and impaired osteogenic differentiation in mesenchymal stem cells endowing leukemic cells with functional advantages. Stem Cells International, 2019, 3864948. https://doi.org/10.1155/2019/3864948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

K.V. and K.M.M. are supported by Early Career Cancer Research Fellowships from the Cancer Council SA Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health. V.P. is supported by a National Health and Medical Research Council Early Career Fellowship. This research was supported in part by a research grant from the Ray and Shirl Norman Cancer Research Trust and by grant 2013025 awarded through the 2021 Priority-driven Collaborative Cancer Research Scheme and co-funded by Cancer Australia and the Leukaemia Foundation.

Author information

Author notes

  1. Andrew C.W. Zannettino and Krzysztof M. Mrozik contributed equally to the work.

Authors and Affiliations

  1. Myeloma Research Laboratory, School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, Level 5 South, SAHMRI, PO Box 11060, Adelaide, SA, 5001, Australia

    Natalya Plakhova, Vasilios Panagopoulos, Kate Vandyke, Andrew C. W. Zannettino & Krzysztof M. Mrozik

  2. Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia

    Natalya Plakhova, Vasilios Panagopoulos, Kate Vandyke, Andrew C. W. Zannettino & Krzysztof M. Mrozik

  3. Central Adelaide Local Health Network, Adelaide, Australia

    Andrew C. W. Zannettino

Authors
  1. Natalya Plakhova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vasilios Panagopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kate Vandyke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew C. W. Zannettino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Krzysztof M. Mrozik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Krzysztof M. Mrozik.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Plakhova, N., Panagopoulos, V., Vandyke, K. et al. Mesenchymal stromal cell senescence in haematological malignancies. Cancer Metastasis Rev 42, 277–296 (2023). https://doi.org/10.1007/s10555-022-10069-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-022-10069-9

Keywords

Search

Navigation