Article | Published:

Acute myeloid leukemia

Transmissible ER stress reconfigures the AML bone marrow compartment

Leukemia (2018) | Download Citation

Abstract

Successive adaptation of the bone marrow (BM) from homeostatic hematopoietic microenvironment to a self-reinforcing niche is an integral aspect of leukemogenesis. Yet, the cellular mechanisms underlying these functional alterations remain to be defined. Here, we found that AML incursion precipitates compartmental endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) in both leukemia and stromal cells. We observed that extracellular vesicles (EV) transmit ER stress in vivo from the AML xenograft to BM stroma, whereby the upregulation of core UPR components drives subsequent osteolineage differentiation of mesenchymal stem cells (MSC). Finally, we show that the underlying mechanism involves quantitative incorporation and cell–cell transfer of Bone Morphogenic Protein 2 (BMP2), a potent osteogenic signal, by AML-EVs. Corroborative studies in AML patient samples support the translational relevance of AML-EVs as a platform for BMP trafficking and source of compartmental crosstalk. Transmissible ER stress was previously identified as a source of chemoresistance in solid tumor models, and this work reveals a role in remodeling the BM niche in AML.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466:829–34.

  2. 2.

    Chitteti BR, Cheng YH, Poteat B, Rodriguez-Rodriguez S, Goebel WS, Carlesso N, et al. Impact of interactions of cellular components of the bone marrow microenvironment on hematopoietic stem and progenitor cell function. Blood. 2010;115:3239–48.

  3. 3.

    Jung Y, Song J, Shiozawa Y, Wang J, Wang Z, Williams B, et al. Hematopoietic stem cells regulate mesenchymal stromal cell induction into osteoblasts thereby participating in the formation of the stem cell niche. Stem Cells. 2008;26:2042–51.

  4. 4.

    El-Badri NS, Wang BY, Cherry, Good RA. Osteoblasts promote engraftment of allogeneic hematopoietic stem cells. Exp Hematol. 1998;26:110–6.

  5. 5.

    Mendez-Ferrer S, Chow A, Merad M, Frenette PS. Circadian rhythms influence hematopoietic stem cells. Curr Opin Hematol. 2009;16:235–42.

  6. 6.

    Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505:327–34.

  7. 7.

    Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E, Sipkins DA. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science. 2008;322:1861–5.

  8. 8.

    Boyd AL, Reid JC, Salci KR, Aslostovar L, Benoit YD, Shapovalova Z, et al. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche. Nat Cell Biol. 2017;19:1336–47.

  9. 9.

    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;32:575–587.

  10. 10.

    Miraki-Moud F, Anjos-Afonso F, Hodby KA, Griessinger E, Rosignoli G, Lillington D, et al. Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation. Proc Natl Acad Sci USA. 2013;110:13576–81.

  11. 11.

    Zhang B, Ho YW, Huang Q, Maeda T, Lin A, Lee SU, et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell. 2012;21:577–92.

  12. 12.

    Schepers K, Pietras EM, Reynaud D, Flach J, Binnewies M, Garg T, et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell. 2013;13:285–99.

  13. 13.

    Duan CW, Shi J, Chen J, Wang B, Yu YH, Qin X, et al. Leukemia propagating cells rebuild an evolving niche in response to therapy. Cancer Cell. 2014;25:778–93.

  14. 14.

    Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25:1315–21.

  15. 15.

    Chandran P, Le Y, Li Y, Sabloff M, Mehic J, Rosu-Myles M, et al. Mesenchymal stromal cells from patients with acute myeloid leukemia have altered capacity to expand differentiated hematopoietic progenitors. Leuk Res. 2015;39:486–93.

  16. 16.

    Reikvam H, Brenner AK, Hagen KM, Liseth K, Skrede S, Hatfield KJ, et al. The cytokine-mediated crosstalk between primary human acute myeloid cells and mesenchymal stem cells alters the local cytokine network and the global gene expression profile of the mesenchymal cells. Stem Cell Res. 2015;15:530–41.

  17. 17.

    Huang JC, Basu SK, Zhao X, Chien S, Fang M, Oehler VG, et al. Mesenchymal stromal cells derived from acute myeloid leukemia bone marrow exhibit aberrant cytogenetics and cytokine elaboration. Blood Cancer J. 2015;5:e302.

  18. 18.

    Passaro D, Di Tullio A, Abarrategi A, Rouault-Pierre K, Foster K, Ariza-McNaughton L, et al. Increased vascular permeability in the bone marrow microenvironment contributes to disease progression and drug response in acute myeloid leukemia. Cancer Cell. 2017;32:324–341

  19. 19.

    Frisch BJ, Ashton JM, Xing L, Becker MW, Jordan CT, Calvi LM. Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia. Blood. 2012;119:540–50.

  20. 20.

    Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA, et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature. 2010;464:852–7.

  21. 21.

    Battula VL, Le PM, Sun JC, Nguyen K, Yuan B, Zhou X, et al. AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth. JCI Insight. 2017;2:13.

  22. 22.

    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.

  23. 23.

    Mirantes C, Passegue E, Pietras EM. Pro-inflammatory cytokines: emerging players regulating HSC function in normal and diseased hematopoiesis. Exp Cell Res. 2014;329:248–54.

  24. 24.

    Rodvold JJ, Chiu KT, Hiramatsu N, Nussbacher JK, Galimberti V, Mahadevan NR, et al. Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells. Sci Signal. 2017;10:482.

  25. 25.

    Rodvold JJ, Mahadevan NR, Zanetti M. Immune modulation by ER stress and inflammation in the tumor microenvironment. Cancer Lett. 2016;380:227–36.

  26. 26.

    Tohmonda T, Miyauchi Y, Ghosh R, Yoda M, Uchikawa S, Takito J, et al. The IRE1alpha-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix. EMBO Rep. 2011;12:451–7.

  27. 27.

    Horiuchi K, Tohmonda T, Morioka H. The unfolded protein response in skeletal development and homeostasis. Cell Mol Life Sci. 2016;73:2851–69.

  28. 28.

    Moore KA, Hollien J. The unfolded protein response in secretory cell function. Annu Rev Genet. 2012;46:165–83.

  29. 29.

    Hornick NI, Doron B, Abdelhamed S, Huan J, Harrington CA, Shen R, et al. AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Sci Signal. 2016;9:ra88.

  30. 30.

    Huan J, Hornick NI, Goloviznina NA, Kamimae-Lanning AN, David LL, Wilmarth PA, et al. Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes. Leukemia. 2015;29:2285–95.

  31. 31.

    Doron B, Handu M, Kurre P. Concise review: adaptation of the bone marrow stroma in hematopoietic malignancies: current concepts and models. Stem Cells. 2017;36:304–312

  32. 32.

    Su X, Yu M, Qiu G, Zheng Y, Chen Y, Wen R, et al. Evaluation of nestin or osterix promoter-driven cre/loxp system in studying the biological functions of murine osteoblastic cells. Am J Transl Res. 2016;8:1447–59.

  33. 33.

    Hornick NI, Huan J, Doron B, Goloviznina NA, Lapidus J, Chang BH, et al. Serum exosome MicroRNA as a minimally-invasive early biomarker of AML. Sci Rep. 2015;5:11295.

  34. 34.

    Hawkins ED, Duarte D, Akinduro O, Khorshed RA, Passaro D, Nowicka M, et al. T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments. Nature. 2016;538:518–22.

  35. 35.

    Boot-Handford RP, Briggs MD. The unfolded protein response and its relevance to connective tissue diseases. Cell Tissue Res. 2010;339:197–211.

  36. 36.

    Hamamura K, Liu Y, Yokota H. Microarray analysis of thapsigargin-induced stress to the endoplasmic reticulum of mouse osteoblasts. J Bone Miner Metab. 2008;26:231–40.

  37. 37.

    Oslowski CM, Urano F. Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Methods Enzymol. 2011;490:71–92.

  38. 38.

    Heusermann W, Hean J, Trojer D, Steib E, von Bueren S, Graff-Meyer A, et al. Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER. J Cell Biol. 2016;213:173–84.

  39. 39.

    Riggs AC, Bernal-Mizrachi E, Ohsugi M, Wasson J, Fatrai S, Welling C, et al. Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis. Diabetologia. 2005;48:2313–21.

  40. 40.

    Shim SH, Xia C, Zhong G, Babcock HP, Vaughan JC, Huang B, et al. Super-resolution fluorescence imaging of organelles in live cells with photoswitchable membrane probes. Proc Natl Acad Sci Usa. 2012;109:13978–83.

  41. 41.

    Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35.

  42. 42.

    Mulcahy LA, Pink RC, Carter DR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014;4:3.

  43. 43.

    Zanetti M, Rodvold JJ, Mahadevan NR. The evolving paradigm of cell-nonautonomous UPR-based regulation of immunity by cancer cells. Oncogene. 2016;35:269–78.

  44. 44.

    Kanemoto S, Nitani R, Murakami T, Kaneko M, Asada R, Matsuhisa K, et al. Multivesicular body formation enhancement and exosome release during endoplasmic reticulum stress. Biochem Biophys Res Commun. 2016;480:166–72.

  45. 45.

    Hara Y, Yamato G, Shiba N, Ohki K, Park M-J, Tomizawa D, et al. High BMP2 expression is a poor prognostic factor and a good candidate to identify CBFA2T3-GLIS2-like high-risk subgroup in pediatric acute myeloid leukemia. Blood. 2015;126:2583.

  46. 46.

    Krause DS, Scadden DT. A hostel for the hostile: the bone marrow niche in hematologic neoplasms. Haematologica. 2015;100:1376–87.

  47. 47.

    Huan J, Hornick NI, Shurtleff MJ, Skinner AM, Goloviznina NA, Roberts CT, et al. RNA trafficking by acute myelogenous leukemia exosomes. Cancer Res. 2013;73:918–29.

  48. 48.

    Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.

  49. 49.

    Duarte D, Hawkins ED, Akinduro O, Ang H, De Filippo K, Kong IY, et al. Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell. 2018;22:64–77.e6.

  50. 50.

    Yadav RK, Chae SW, Kim HR, Chae HJ. Endoplasmic reticulum stress and cancer. J Cancer Prev. 2014;19:75–88.

  51. 51.

    Schardt JA, Mueller BU, Pabst T. Activation of the unfolded protein response in human acute myeloid leukemia. Methods Enzymol. 2011;489:227–43.

  52. 52.

    Sun H, Lin DC, Guo X, Kharabi Masouleh B, Gery S, Cao Q, et al. Inhibition of IRE1alpha-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia. Oncotarget. 2016;7:18736–49.

  53. 53.

    Wey S, Luo B, Tseng CC, Ni M, Zhou H, Fu Y, et al. Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling. Blood. 2012;119:817–25.

  54. 54.

    Murakami T, Saito A, Hino S, Kondo S, Kanemoto S, Chihara K, et al. Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation. Nat Cell Biol. 2009;11:1205–11.

  55. 55.

    Montgomery TA, Ruvkun G. MicroRNAs visit the ER. Cell . 2013;153:511–2.

  56. 56.

    Stalder L, Heusermann W, Sokol L, Trojer D, Wirz J, Hean J, et al. The rough endoplasmatic reticulum is a central nucleation site of siRNA-mediated RNA silencing. EMBO J. 2013;32:1115–27.

  57. 57.

    Zylbersztejn F, Flores-Violante M, Voeltzel T, Nicolini FE, Lefort S, Maguer-Satta V. The BMP pathway: a unique tool to decode the origin and progression of leukemia. Exp Hematol. 2018;61:36–44

  58. 58.

    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.

  59. 59.

    Krause DS, Fulzele K, Catic A, Sun CC, Dombkowski D, Hurley MP, et al. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat Med. 2013;19:1513–7.

  60. 60.

    Raaijmakers MH. Niche contributions to oncogenesis: emerging concepts and implications for the hematopoietic system. Haematologica. 2011;96:1041–8.

  61. 61.

    Viola S, Traer E, Huan J, Hornick NI, Tyner JW, Agarwal A, et al. Alterations in acute myeloid leukaemia bone marrow stromal cell exosome content coincide with gains in tyrosine kinase inhibitor resistance. Br J Haematol. 2016;172:983–6.

Download references

Acknowledgements

We are indebted to staff in the Department of Comparative Medicine for excellent veterinary care, the technicians at the OHSU Flow Cytometry core, and acknowledge contributions by all members of the labs. These studies were funded in part by: Hyundai Hope on Wheels (PK), Max Blue Butterfly Campaign (PK), R01-CA164024 (TMH), and Hyundai Hope on Wheels grant (TMH).

Author contributions

BD conceived the study, designed and performed the experiments, analyzed data, interpreted the results, and wrote the paper; SA performed xenograft studies, intrafemoral injections, and helped with experiments; JTB performed microscopy and in vitro experiments, analyzed the data, generated figures and edited the manuscript; SKH organized, generated and interpreted patient data, and edited the manuscript; TMH consented patients, supervised patient data collection and experiments, interpreted patient data, and edited the manuscript; PK conceived the study, designed the experiments, interpreted the results, wrote the paper, and oversaw the research project.

Author information

Affiliations

  1. Department of Pediatrics, Pediatric Blood & Cancer Biology Program, Papé Family Pediatric Research Institute, Portland, OR, USA

    • Ben Doron
    • , Sherif Abdelhamed
    • , John T. Butler
    •  & Peter Kurre
  2. OHSU Knight Cancer Institute, Portland, OR, USA

    • Ben Doron
    • , Sherif Abdelhamed
    • , John T. Butler
    •  & Peter Kurre
  3. Department of Biomedical Engineering, Portland, OR, USA

    • Ben Doron
    • , Sherif Abdelhamed
    • , John T. Butler
    •  & Peter Kurre
  4. Oregon Health & Science University, Portland, OR, USA

    • John T. Butler
  5. Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA

    • Saman K. Hashmi
    •  & Terzah M. Horton
  6. Division of Hematology, The Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, ARC 302, Philadelphia, 19104, PA, USA

    • Peter Kurre

Authors

  1. Search for Ben Doron in:

  2. Search for Sherif Abdelhamed in:

  3. Search for John T. Butler in:

  4. Search for Saman K. Hashmi in:

  5. Search for Terzah M. Horton in:

  6. Search for Peter Kurre in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Peter Kurre.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41375-018-0254-2