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Myelodysplastic syndrome

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

Leukemia volume 34, pages 2460–2472 (2020)Cite this article

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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.

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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.

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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.

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Author notes

  1. These authors contributed equally: Stephanie L. Tzetzo, Eduardo Cortes Gomez, Kevin H. Eng

  2. These authors jointly supervised this work: Elizabeth A. Griffiths, Michael J. Nemeth

Authors and Affiliations

  1. Department of Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Pragya Srivastava, Kyle R. Wiatrowski, Jennifer Peresie, Ava Dimitroff, Elizabeth A. Griffiths & Michael J. Nemeth

  2. Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Stephanie L. Tzetzo, Scott I. Abrams & Michael J. Nemeth

  3. Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Eduardo Cortes Gomez, Kevin H. Eng, Miranda L. Lynch & Jianmin Wang

  4. Department of Pathology and Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Sheila N. Jani Sait

  5. Department of Orthopaedics, University at Buffalo, Buffalo, NY, USA

    Joseph B. Kuechle

  6. Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Prashant K. Singh

  7. Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Kitty De Jong

  8. Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Elizabeth A. Griffiths

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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.

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

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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).

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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

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