Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Myelodysplastic syndrome

Inhibition of LSD1 in MDS progenitors restores differentiation of CD141Hi conventional dendritic cells

Abstract

The use of immunotherapy to treat patients with myelodysplastic syndromes (MDS) shows promise but is limited by our incomplete understanding of the immunologic milieu. In solid tumors, CD141Hi conventional dendritic cells (CD141Hi cDCs) are necessary for antitumor immunosurveillance and the response to immunotherapy. Here, we found that CD141Hi cDCs are reduced in MDS bone marrow and based on the premise established in solid tumors, we hypothesized that reduced numbers of CD141Hi cDCs are associated with inferior overall survival in MDS patients. We found that MDS patients with reduced numbers of CD141Hi cDCs, but not other DC populations, showed reduced overall survival. To examine the basis for reduction in CD141Hi cDCs, we found fewer numbers of progenitors committed to DC differentiation in the MDS bone marrow and these progenitors expressed lower levels of interferon regulatory factor-8 (IRF8), a master regulator of CD141Hi cDC differentiation. To rescue impaired CD141Hi cDC differentiation, we used pharmacologic inhibition of lysine-specific demethylase 1A (LSD1) to promote CD141Hi cDC differentiation by MDS progenitors. These data reveal a previously unrecognized element of the MDS immunologic milieu. Epigenetic regulation of CD141Hi cDC differentiation offers an intriguing opportunity for intervention and a potential adjunct to immunotherapy for patients with MDS.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Lower numbers of CD141Hi conventional dendritic cells are associated with decreased overall survival of MDS patients.
Fig. 2: MDS patients exhibit decreased numbers of dendritic cell committed progenitors and decreased expression of IRF8.
Fig. 3: LSD1 inhibition enhances CD141Hi cDC differentiation of MDS CD34+ progenitors.
Fig. 4: LSD1 inhibition enhances IRF8 expression and promotes histone acetylation and demethylation at the IRF8 locus.
Fig. 5: LSD1 inhibition requires IRF8 for effect on CD24+ cDC differentiation.

References

  1. 1.

    Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109:1536–42.

    PubMed  Google Scholar 

  2. 2.

    Nachtkamp K, Stark R, Strupp C, Kündgen A, Giagounidis A, Aul C, et al. Causes of death in 2877 patients with myelodysplastic syndromes. Ann Hematol. 2016;95:937–44.

    PubMed  Google Scholar 

  3. 3.

    Nieto M, Demolis P, Béhanzin E, Moreau A, Hudson I, Flores B, et al. The European medicines agency review of decitabine (Dacogen) for the treatment of adult patients with acute myeloid leukemia: summary of the scientific assessment of the committee for medicinal products for human use. Oncologist. 2016;21:692–700.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Jabbour E, Garcia-Manero G, Batty N, Shan J, O’Brien S, Cortes J, et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010;116:3830–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Daver N, Garcia-Manero G, Basu S, Boddu PC, Alfayez M, Cortes JE, et al. Efficacy, Safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a nonrandomized, open-label, phase II study. Cancer Disco. 2018;9:1–15.

    Google Scholar 

  6. 6.

    Griffiths EA, Srivastava P, Matsuzaki J, Brumberger Z, Wang ES, Kocent J, et al. NY-ESO-1 vaccination in combination with decitabine induces antigen-specific t-lymphocyte responses in patients with myelodysplastic syndrome. Clin Cancer Res. 2018;24:1019–29.

    CAS  PubMed  Google Scholar 

  7. 7.

    Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2019;144:646–18.

    Google Scholar 

  8. 8.

    Broz ML, Binnewies M, Boldajipour B, Nelson AE, Pollack JL, Erle DJ, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell. 2014;26:638–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Roberts EW, Broz ML, Binnewies M, Headley MB, Nelson AE, Wolf DM, et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for Tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell. 2016;30:324–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Barry KC, Hsu J, Broz ML, Cueto FJ, Binnewies M, Combes AJ, et al. A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments. Nat Med. 2018;24:1–21.

    Google Scholar 

  11. 11.

    Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol. 2014;14:571–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science. 2008;322:1097–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CMT, Pryer N, et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell. 2014;26:623–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Mittal D, Vijayan D, Putz EM, Aguilera AR, Markey KA, Straube J, et al. Interleukin-12 from CD103+ Batf3-dependent dendritic cells required for NK-Cell suppression of metastasis. Cancer Immunol Res. 2017;5:1098–108.

    CAS  PubMed  Google Scholar 

  15. 15.

    Sánchez-Paulete AR, Cueto FJ, Martínez-López M, Labiano S, Morales-Kastresana A, Rodríguez-Ruiz ME, et al. Cancer Immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Disco. 2016;6:71–9.

    Google Scholar 

  16. 16.

    Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R, Jordan S, et al. Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity. 2016;44:924–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Spranger S, Dai D, Horton B, Gajewski TF. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell. 2017;31:711–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Kerkhoff N, Bontkes HJ, Westers TM, de Gruijl TD, Kordasti S, van de Loosdrecht AA. Dendritic cells in myelodysplastic syndromes: from pathogenesis to immunotherapy. Immunotherapy. 2013;5:621–37.

    CAS  PubMed  Google Scholar 

  19. 19.

    Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81:515–26.

    Google Scholar 

  20. 20.

    Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Epling-Burnette PK, Bai F, Painter JS, Rollison DE, Salih HR, Krusch M, et al. Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood. 2007;109:4816–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Hémont C, Neel A, Heslan M, Braudeau C, Josien R. Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness. J Leukoc Biol. 2013;93:599–609.

    PubMed  Google Scholar 

  23. 23.

    Chiang M-C, Tullett KM, Lee YS, Idris A, Ding Y, McDonald KJ, et al. Differential uptake and cross-presentation of soluble and necrotic cell antigen by human DC subsets. Eur J Immunol. 2016;46:329–39.

    CAS  PubMed  Google Scholar 

  24. 24.

    Thompson JE, Conlon JP, Yang X, Sanchez PV, Carroll M. Enhanced growth of myelodysplastic colonies in hypoxic conditions. Exp Hematol. 2007;35:21–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Lee J, Zhou YJ, Ma W, Zhang W, Aljoufi A, Luh T, et al. Lineage specification of human dendritic cells is marked by IRF8 expression in hematopoietic stem cells and multipotent progenitors. Nat Immunol. 2017;18:877–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Sichien D, Scott CL, Martens L, Vanderkerken M, Van Gassen S, Plantinga M, et al. IRF8 transcription factor controls survival and function of terminally differentiated conventional and plasmacytoid dendritic cells, respectively. Immunity. 2016;45:626–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Grajales-Reyes GE, Iwata A, Albring J, Wu X, Tussiwand R, Kc W, et al. Batf3 maintains autoactivation of Irf8 for commitment of a CD8α(+) conventional DC clonogenic progenitor. Nat Immunol. 2015;16:708–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Schmidt M, Nagel S, Proba J, Thiede C, Ritter M, Waring JF, et al. Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias. Blood. 1998;91:22–9.

    CAS  PubMed  Google Scholar 

  29. 29.

    Waight JD, Banik D, Griffiths EA, Nemeth MJ, Abrams SI. Regulation of the interferon regulatory factor-8 (IRF-8) tumor suppressor gene by the signal transducer and activator of transcription 5 (STAT5) transcription factor in chronic myeloid leukemia. J Biol Chem. 2014;289:15642–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Will B, Vogler TO, Narayanagari S, Bartholdy B, Todorova TI, da Silva Ferreira M, et al. Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia. Nat Med. 2015;21:1172–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Gaillard C, Surianarayanan S, Bentley T, Warr MR, Fitch B, Geng H, et al. Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia. Blood Adv. 2018;2:2462–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Schenk T, Chen WC, Göllner S, Howell L, Jin L, Hebestreit K, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012;18:605–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012;21:473–87.

    CAS  PubMed  Google Scholar 

  34. 34.

    Maes T, Mascaró C, Tirapu I, Estiarte A, Ciceri F, Lunardi S, et al. ORY-1001, a potent and selective covalent KDM1A inhibitor, for the treatment of acute leukemia. Cancer Cell. 2018;33:495–511.

    CAS  PubMed  Google Scholar 

  35. 35.

    Cusan M, Cai SF, Mohammad HP, Krivtsov A, Chramiec A, Loizou E, et al. LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML. Blood. 2018;131:1730–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Olsson A, Venkatasubramanian M, Chaudhri VK, Aronow BJ, Salomonis N, Singh H, et al. Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature. 2016;537:698–702.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Maiques-Diaz A, Spencer GJ, Lynch JT, Ciceri F, Williams EL, Amaral FMR, et al. Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia. Cell Rep. 2018;22:3641–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Barth J, Abou-El-Ardat K, Dalic D, Kurrle N, Maier A-M, Mohr S, et al. LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML. Leukemia. 2019;33:1411–26.

    CAS  PubMed  Google Scholar 

  39. 39.

    Bell CC, Fennell KA, Chan Y-C, Rambow F, Yeung MM, Vassiliadis D, et al. Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia. Nat Comm. 2019;10:2723.

    Google Scholar 

  40. 40.

    Lee J, Breton G, Aljoufi A, Zhou YJ, Puhr S, Nussenzweig MC, et al. Clonal analysis of human dendritic cell progenitor using a stromal cell culture. J Immunol Methods. 2015;425:21–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Rouault-Pierre K, Mian SA, Goulard M, Abarrategi A, Di Tulio A, Smith AE, et al. Preclinical modeling of myelodysplastic syndromes. Leukemia. 2017;31:2702–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Mohammad HP, Smitheman KN, Kamat CD, Soong D, Federowicz KE, Van Aller GS, et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell. 2015;28:57–69.

    CAS  PubMed  Google Scholar 

  43. 43.

    Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. 2010;207:1247–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Duy C, Teater M, Garrett-Bakelman FE, Lee TC, Meydan C, Glass JL, et al. Rational targeting of cooperating layers of the epigenome yields enhanced therapeutic efficacy against AML. Cancer Discov. 2019;9:872–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Kurotaki D, Kawase W, Sasaki H, Nakabayashi J, Nishiyama A, Morse HC, et al. Epigenetic control of early dendritic cell lineage specification by the transcription factor IRF8 in mice. Blood. 2019;133:1803–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Ganan-Gomez I, Wei Y, Starczynowski DT, Colla S, Yang H, Cabrero-Calvo M, et al. Deregulation of innate immune and inflammatory signaling in MDS. Leukemia. 2015;29:1458–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Kordasti SY, Ingram W, Hayden J, Darling D, Barber L, Afzali B, et al. CD4+CD25high Foxp3+ regulatory T cells in myelodysplastic syndrome (MDS). Blood. 2007;110:847–50.

    CAS  PubMed  Google Scholar 

  48. 48.

    Chen X, Eksioglu EA, Zhou J, Zhang L, Djeu J, Fortenbery N, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest. 2013;123:4595–611.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Saft L, Björklund E, Berg E, Hellström-Lindberg E, Porwit A. Bone marrow dendritic cells are reduced in patients with high-risk myelodysplastic syndromes. Leuk Res. 2013;37:266–73.

    CAS  PubMed  Google Scholar 

  50. 50.

    Kline DE, MacNabb BW, Chen X, Chan W-C, Fosco D, Kline J. CD8α+ dendritic cells dictate leukemia-specific CD8+ T cell fates. J Immunol. 2018;201:3759–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Scott CL, Soen B, Martens L, Skrypek N, Saelens W, Taminau J, et al. The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2. J Exp Med. 2016;213:897–911.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Liu Y, Bewersdorf JP, Stahl M, Zeidan AM. Immunotherapy in acute myeloid leukemia and myelodysplastic syndromes: the dawn of a new era? Blood Rev. 2019;34:67–83.

    CAS  PubMed  Google Scholar 

  53. 53.

    Sheng W, LaFleur MW, Nguyen TH, Chen S, Chakravarthy A, Conway JR, et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell. 2018;174:549–63.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

First, we thank our patients and their families. We acknowledge the contributions of the Hematologic Procurement Resource at Roswell Park: Laurie Ann Ford, Tara Cronin, Linda G. Lutgen-Dunckley, Brandon L. Martens, and Joseph R. Moberg. We thank Philip L. McCarthy, George L. Chen, Maureen Ross, Barbara J. Bambach, Stephen Schinnagel, and Mary Bayers-Thering for sourcing de-identified healthy donor specimens. We thank our research coordinators Krista Belko and Justin Kocent. We thank Renae Holtz for assistance with shRNA studies and Scott Portwood and Eunice S. Wang for assistance with hypoxia studies. We thank Kelvin Lee for KG-1 cells. We acknowledge Tim Somervaille for helpful discussions. We thank David Eifrig and Charles Flippen for editorial assistance. This work was funded by the Roswell Park Alliance Foundation (EAG and MJN), the Rapaport Foundation (EAG and MJN), NIH grant 5T32 CA085183-17 (SLT), and NIH grant R01 CA172105 (SIA). This work was supported by National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park Flow and Image Cytometry, Bioinformatics, Biostatistics, Laboratory Animal, and Genomics Shared Resources.

Author information

Affiliations

Authors

Contributions

PS, EAG, and MJN designed the experiments. PS, SLT, SNJS, and MJN performed experiments. PS, SLT, ECG, KHE, MLL, JW, EAG, and MJN analyzed the data. PKS, KDJ, KRW, AD, SP, and JP provided assistance with experiments. JBK provided critical reagents. PS, EAG, and MJN wrote the manuscript with editorial contributions and review from all authors.

Corresponding authors

Correspondence to Elizabeth A. Griffiths or Michael J. Nemeth.

Ethics declarations

Conflict of interest

EAG: Advisory Board/Honoraria: Celgene (Relevant), Boston Scientific, Persimmune, New Link Genetics, Astex/Otsuka (Relevant), Partner Therapeutics, Inc., Alexion Pharmaceuticals, Abbvie, Novartis. Research Funding/Clinical Trials: Astex Pharmaceuticals (clinical trial PI), Celgene (clinical trial PI, research funding), Genentech (research funding), Appelis pharmaceuticals (clinical trial PI). MJN: Genentech (research funding).

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Srivastava, P., Tzetzo, S.L., Gomez, E.C. et al. Inhibition of LSD1 in MDS progenitors restores differentiation of CD141Hi conventional dendritic cells. Leukemia 34, 2460–2472 (2020). https://doi.org/10.1038/s41375-020-0765-5

Download citation

Search

Quick links