Abstract
The fate of leukaemia stem cells (LSCs) is determined by both their inherent mechanisms and crosstalk with their niches. Although LSCs were confirmed to be eradicated by restarting senescence, the specific key regulators of LSC resistance to senescence and remodelling of the niche to obtain a microenvironment suitable for stemness remain unknown. Here, we found that RAB27B, a gene regulating exosome secretion, was overexpressed in LSCs and associated with the poor prognosis of acute myeloid leukaemia (AML) patients. The increased RAB27B in LSCs prevented their senescence and maintained their stemness in vitro and in vivo. Mechanically, the increased RAB27B expression in LSCs selectively promoted the loading and release of exosomes rich in senescence-inducing proteins by direct combination. Furthermore, RAB27B-regulated LSC-derived exosomes remodelled the niche and induced senescence of mesenchymal stem cells (MSCs) with increased RAB27B expression ex vivo and in vivo. The increased RAB27B in the senescent MSCs conversely promoted LSC maintenance ex vivo and in vivo via selective excretion of exosomes rich in stemness-promoting proteins. Therefore, we identified the specifically increased RAB27B in LSCs and their educated senescent MSCs as a hub molecule for LSC resistance to senescence and maintenance through crosstalk with its niche via selective exosome excretion.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The raw data of RNA-seq were deposited in NCBI SRA database with accession number PRJNA1028544 and PRJNA1029326. The mass spectrometry proteomics data were deposited to the ProteomeXchange Consortium via the iProX partner repository [58, 59] with the dataset identifier PXD046222 and PXD046223. For original data, please contact liulingbo@hust.edu.cn.
References
Lytle NK, Barber AG, Reya T. Stem cell fate in cancer growth, progression and therapy resistance. Nat Rev Cancer. 2018;18:669–80.
MacPherson L, Anokye J, Yeung MM, Lam EYN, Chan Y, Weng C, et al. Hbo1 is required for the maintenance of leukaemia stem cells. Nature. 2020;577:266–70.
Shlush LI, Mitchell A, Heisler L, Abelson S, Ng S, Trotman-Grant A, et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017;547:104–8.
Trumpp A, Haas S. Cancer stem cells: the adventurous journey from hematopoietic to leukemic stem cells. Cell. 2022;185:1266–70.
Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: defining a path forward. Cell. 2019;179:813–27.
Ruscetti M, Morris JP, Mezzadra R, Russell J, Leibold J, Romesser PB, et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell. 2020;181:424–41.
Schmitt CA, Wang B, Demaria M. Senescence and cancer - role and therapeutic opportunities. Nat Rev Clin Oncol. 2022;19:619–36.
Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nat Rev Cancer. 2022;22:340–55.
Niu J, Peng D, Liu L. Drug resistance mechanisms of acute myeloid leukemia stem cells. Front Oncol. 2022;12:896426.
Bourdeau V, Ferbeyre G. Engaging a senescent response to cure leukemia. Nat Med. 2014;20:123–4.
Peng D, Wang H, Li L, Ma X, Chen Y, Zhou H, et al. Mir-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective rab27b targeting to inhibit exosome shedding. Leukemia. 2018;32:1180–8.
Abdul-Aziz AM, Sun Y, Hellmich C, Marlein CR, Mistry J, Forde E, et al. Acute myeloid leukemia induces protumoral p16ink4a-driven senescence in the bone marrow microenvironment. Blood. 2019;133:446–56.
Kumar B, Garcia M, Weng L, Jung X, Murakami JL, Hu X, et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia. 2018;32:575–87.
Lim M, Pang Y, Ma S, Hao S, Shi H, Zheng Y, et al. Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow. Leukemia. 2016;30:154–62.
Geyh S, Rodriguez-Paredes M, Jager P, Khandanpour C, Cadeddu RP, Gutekunst J, et al. Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. Leukemia. 2016;30:683–91.
Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30.
Yang J, Zhang G, Zhang Q, Zhang Y, Zhang Z, Ni X, et al. Zip4 promotes muscle wasting and cachexia in mice with orthotopic pancreatic tumors by stimulating rab27b-regulated release of extracellular vesicles from cancer cells. Gastroenterology. 2019;156:722–34.
Song L, Tang S, Han X, Jiang Z, Dong L, Liu C, et al. Kibra controls exosome secretion via inhibiting the proteasomal degradation of rab27a. Nat Commun. 2019;10:1639.
Fujii M, Kawai Y, Endoh M, Hossain MN, Nakabayashi K, Ayusawa D. Expression of rab27b is up-regulated in senescent human cells. Mech Ageing Dev. 2006;127:639–42.
Crescitelli R, Lässer C, Szabó TG, Kittel A, Eldh M, Dianzani I, et al. Distinct rna profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J Extracell Vesicles. 2013;2:20677.
Wen J, Chen Y, Liao C, Ma X, Wang M, Li Q, et al. Engineered mesenchymal stem cell exosomes loaded with mir-34c-5p selectively promote eradication of acute myeloid leukemia stem cells. Cancer Lett. 2023;575:216407.
Jing B, Qian R, Jiang D, Gai Y, Liu Z, Guo F, et al. Extracellular vesicles-based pre-targeting strategy enables multi-modal imaging of orthotopic colon cancer and image-guided surgery. J Nanobiotechnology. 2021;19:151.
Mercier FE, Shi J, Sykes DB, Oki T, Jankovic M, Man CH, et al. In vivo genome-wide crispr screening in murine acute myeloid leukemia uncovers microenvironmental dependencies. Blood Adv. 2022;6:5072–84.
Ng SW, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016;540:433–7.
van Galen P, Hovestadt V, Wadsworth IM, Hughes TK, Griffin GK, Battaglia S, et al. Single-cell rna-seq reveals aml hierarchies relevant to disease progression and immunity. Cell. 2019;176:1265–81.
Saul D, Kosinsky RL, Atkinson EJ, Doolittle ML, Zhang X, LeBrasseur NK, et al. A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nat Commun. 2022;13:4827.
Leidal AM, Huang HH, Marsh T, Solvik T, Zhang D, Ye J, et al. The lc3-conjugation machinery specifies the loading of rna-binding proteins into extracellular vesicles. Nat Cell Biol. 2020;22:187–99.
Zeng Q, Saghafinia S, Chryplewicz A, Fournier N, Christe L, Xie Y, et al. Aberrant hyperexpression of the rna binding protein fmrp in tumors mediates immune evasion. Science. 2022;378:eabl7207.
Guo D, Lui G, Lai SL, Wilmott JS, Tikoo S, Jackett LA, et al. Rab27a promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes. Int J Cancer. 2019;144:3070–85.
Borghesan M, Fafián-Labora J, Eleftheriadou O, Carpintero-Fernández P, Paez-Ribes M, Vizcay-Barrena G, et al. Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein ifitm3. Cell Rep. 2019;27:3956–71.
Zhang M, Liu L, Lin X, Wang Y, Li Y, Guo Q, et al. A translocation pathway for vesicle-mediated unconventional protein secretion. Cell. 2020;181:637–52.
Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of exosome composition. Cell. 2019;177:428–45.
Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28:436–53.
Weng Z, Wang Y, Ouchi T, Liu H, Qiao X, Wu C, et al. Mesenchymal stem/stromal cell senescence: hallmarks, mechanisms, and combating strategies. Stem Cells Transl Med. 2022;11:356–71.
Duy C, Li M, Teater M, Meydan C, Garrett-Bakelman FE, Lee TC, et al. Chemotherapy induces senescence-like resilient cells capable of initiating aml recurrence. Cancer Discov. 2021;11:1542–61.
Rapisarda V, Borghesan M, Miguela V, Encheva V, Snijders AP, Lujambio A, et al. Integrin beta 3 regulates cellular senescence by activating the tgf-β pathway. Cell Rep. 2017;18:2480–93.
Fregoso OI, Das S, Akerman M, Krainer AR. Splicing-factor oncoprotein srsf1 stabilizes p53 via rpl5 and induces cellular senescence. Mol Cell. 2013;50:56–66.
Narita M, Narita M, Krizhanovsky V, Nuñez S, Chicas A, Hearn SA, et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell. 2006;126:503–14.
Schreiber M, Muller WJ, Singh G, Graham FL. Comparison of the effectiveness of adenovirus vectors expressing cyclin kinase inhibitors p16ink4a, p18ink4c, p19ink4d, p21waf1/cip1 and p27kip1 in inducing cell cycle arrest, apoptosis and inhibition of tumorigenicity. Oncogene. 1999;18:1663–76.
Zarneshan SN, Fakhri S, Bachtel G, Bishayee A. Exploiting pivotal mechanisms behind the senescence-like cell cycle arrest in cancer. Adv Protein Chem Struct Biol. 2023;135:1–19.
Jin Y, Lee H, Zeng SX, Dai MS, Lu H. Mdm2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. Embo J. 2003;22:6365–77.
Mering CV. String: a database of predicted functional associations between proteins. Nucleic Acids Res. 2003;31:258–61.
Lei Q, Gao F, Liu T, Ren W, Chen L, Cao Y, et al. Extracellular vesicles deposit pcna to rejuvenate aged bone marrow-derived mesenchymal stem cells and slow age-related degeneration. Sci Transl Med. 2021;13:eaaz8697.
Dai J, Escara-Wilke J, Keller JM, Jung Y, Taichman RS, Pienta KJ, et al. Primary prostate cancer educates bone stroma through exosomal pyruvate kinase m2 to promote bone metastasis. J Exp Med. 2019;216:2883–99.
Yuan H, Yan M, Zhang G, Liu W, Deng C, Liao G, et al. Cancersea: a cancer single-cell state atlas. Nucleic Acids Res. 2019;47:D900–D908.
Zou W, Lai M, Jiang Y, Mao L, Zhou W, Zhang S, et al. Exosome release delays senescence by disposing of obsolete biomolecules. Adv Sci (Weinh). 2023;10:e2204826.
Wallis R, Josipovic N, Mizen H, Robles-Tenorio A, Tyler EJ, Papantonis A, et al. Isolation methodology is essential to the evaluation of the extracellular vesicle component of the senescence-associated secretory phenotype. J Extracell Vesicles. 2021;10:e12041.
Tolmachova T, Abrink M, Futter CE, Authi KS, Seabra MC. Rab27b regulates number and secretion of platelet dense granules. Proc Natl Acad Sci USA. 2007;104:5872–7.
Shafqat S, Arana CE, Shafqat A, Hashmi SK. The achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence. J Clin Invest. 2022;132:e158452.
Takasugi M, Yoshida Y, Ohtani N. Cellular senescence and the tumour microenvironment. Mol Oncol. 2022;16:3333–51.
Ren J, Xing B, Lv K, O Keefe RA, Wu M, Wang R, et al. Rab27b controls palmitoylation-dependent nras trafficking and signaling in myeloid leukemia. J Clin Invest. 2023;133:e165510.
Shah R, Patel T, Freedman JE. Circulating extracellular vesicles in human disease. N. Engl J Med. 2018;379:958–66.
Mathieu M, Martin-Jaular L, Lavieu G, Théry C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9–17.
Kutyna MM, Kok CH, Lim Y, Tran E, Campbell D, Paton S, et al. A senescence stress secretome is a hallmark of therapy-related myeloid neoplasm stromal tissue occurring soon after cytotoxic exposure. Leukemia. 2022;36:2678–89.
Varela-EirÃn M, Carpintero-Fernández P, Guitián-Caamaño A, Varela-Vázquez A, GarcÃa-Yuste A, Sánchez-Temprano A, et al. Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells contributing to osteoarthritis progression. Cell Death Dis. 2022;13:681.
Prieto LI, Sturmlechner I, Graves SI, Zhang C, Goplen NP, Yi ES, et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell. 2023;41:1261–.e6.
Karantanou C, Minciacchi VR, Kumar R, Zanetti C, Bravo J, PR S, et al. Impact of mesenchymal stromal cell-derived vesicular cargo on B-cell acute lymphoblastic leukemia progression. Blood Adv. 2023;7:1190–1203.
Ma J, Chen T, Wu S, Yang C, Bai M, Shu K, et al. Iprox: an integrated proteome resource. Nucleic Acids Res. 2019;47:D1211–D1217.
Chen T, Ma J, Liu Y, Chen Z, Xiao N, Lu Y, et al. Iprox in 2021: connecting proteomics data sharing with big data. Nucleic Acids Res. 2022;50:D1522–D1527.
Acknowledgements
The authors would like to thank the Nature Research Editing Service for the English language editing (the verification code 397B-FB33-1BAD-BF9D-642P). This work was supported by grants from the National Natural Science Foundation of China ((Nos. 81973999, 81370660 and 82270184 to LL; 81900188 to D.P).
Author information
Authors and Affiliations
Contributions
YC, JW, QL, and DP performed the experiments, analyzed the data and wrote the manuscript. CL, XM, MW, JN, DW, YL and XZ participated in the collection of bone marrow and spleen cells from the NCG mice. LL, JZ and HZ provided critical evaluation of the experimental data and the manuscript. LL conceived the study, analyzed the data and wrote the manuscript.
Corresponding author
Ethics declarations
Competing interests
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.
Supplementary information
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.
About this article
Cite this article
Chen, Y., Wen, J., Li, Q. et al. RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment. Leukemia 38, 266–280 (2024). https://doi.org/10.1038/s41375-023-02097-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-023-02097-3