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ACUTE MYELOID LEUKEMIA

RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment

Leukemia volume 38, pages 266–280 (2024)Cite this article

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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.

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Fig. 1: RAB27B is overexpressed in AML LSCs and associated with poor prognosis in patients with AML.
Fig. 2: RAB27B downregulation induces senescence and loss of stemness in AML LSCs ex vivo.
Fig. 3: RAB27B downregulation in AML LSCs effectively prevents AML development in vivo.
Fig. 4: RAB27B downregulation selectively inhibits the loading and secretion of exosomes rich in senescence-inducing proteins in LSCs.
Fig. 5: AML LSC-derived exosomes selectively lead to BM-MSC senescence in a RAB27B-dependent manner in vitro.
Fig. 6: AML LSC-derived exosomes selectively lead to BM-MSC senescence in a RAB27B-dependent manner in vivo.
Fig. 7: RAB27B-regulated AML LSC-derived exosomes induce BM-MSC senescence mainly through enhancement of the DDR, ROS and PI3K/AKT/mTOR signalling pathways.
Fig. 8: RAB27B-regulated exosome secretion of AML LSC-induced senescent MSCs supports AML LSC proliferation in vitro and AML development in vivo through multifaceted stemness-promoting proteins.

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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

  1. Lytle NK, Barber AG, Reya T. Stem cell fate in cancer growth, progression and therapy resistance. Nat Rev Cancer. 2018;18:669–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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.

    Article  ADS  CAS  PubMed  Google Scholar 

  3. 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.

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Trumpp A, Haas S. Cancer stem cells: the adventurous journey from hematopoietic to leukemic stem cells. Cell. 2022;185:1266–70.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schmitt CA, Wang B, Demaria M. Senescence and cancer - role and therapeutic opportunities. Nat Rev Clin Oncol. 2022;19:619–36.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nat Rev Cancer. 2022;22:340–55.

    Article  CAS  PubMed  Google Scholar 

  9. Niu J, Peng D, Liu L. Drug resistance mechanisms of acute myeloid leukemia stem cells. Front Oncol. 2022;12:896426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bourdeau V, Ferbeyre G. Engaging a senescent response to cure leukemia. Nat Med. 2014;20:123–4.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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.

    Article  ADS  CAS  PubMed  Google Scholar 

  25. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 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.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of exosome composition. Cell. 2019;177:428–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28:436–53.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mering CV. String: a database of predicted functional associations between proteins. Nucleic Acids Res. 2003;31:258–61.

    Article  Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

  46. 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.

    Article  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Takasugi M, Yoshida Y, Ohtani N. Cellular senescence and the tumour microenvironment. Mol Oncol. 2022;16:3333–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shah R, Patel T, Freedman JE. Circulating extracellular vesicles in human disease. N. Engl J Med. 2018;379:958–66.

    Article  CAS  PubMed  Google Scholar 

  53. 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.

    Article  CAS  PubMed  Google Scholar 

  54. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Varela-Eirín M, Carpintero-Fernández P, Guitián-Caamaño A, Varela-Vázquez A, García-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.

    Article  PubMed  PubMed Central  Google Scholar 

  56. 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.

    Article  PubMed  Google Scholar 

  57. 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.

  58. 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.

    Article  PubMed  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

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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).

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  1. These authors contributed equally: Ying Chen, Jin Wen, Qian Li, Danyue Peng.

Authors and Affiliations

  1. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Ying Chen, Jin Wen, Qian Li, Danyue Peng, Chenxi Liao, Xiao Ma, Mengyuan Wang, Jialan Niu, Di Wang, Yingnan Li, Xiaolan Zhang, Hao Zhou, Jing Zou & Lingbo Liu

  2. Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Lei Li

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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.

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Correspondence to Lingbo Liu.

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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

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