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

Authors
  • Srivastava, Pragya1
  • Tzetzo, Stephanie L2
  • Gomez, Eduardo Cortes3
  • Eng, Kevin H3
  • Jani Sait, Sheila N4
  • Kuechle, Joseph B5
  • Singh, Prashant K6
  • De Jong, Kitty7
  • Wiatrowski, Kyle R1
  • Peresie, Jennifer1
  • Dimitroff, Ava1
  • Lynch, Miranda L3
  • Wang, Jianmin3
  • Abrams, Scott I2
  • Griffiths, Elizabeth A8, 9
  • Nemeth, Michael J10, 11
  • 1 Department of Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
  • 2 Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
  • 3 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
  • 4 Department of Pathology and Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
  • 5 Department of Orthopaedics, University at Buffalo, Buffalo, NY, USA.
  • 6 Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
  • 7 Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
  • 8 Department of Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA. [email protected]
  • 9 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA. [email protected]
  • 10 Department of Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA. [email protected]
  • 11 Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA. [email protected]
Type
Published Article
Journal
Leukemia
Publisher
Springer Nature
Publication Date
Sep 01, 2020
Volume
34
Issue
9
Pages
2460–2472
Identifiers
DOI: 10.1038/s41375-020-0765-5
PMID: 32099035
Source
Medline
Language
English
License
Unknown

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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