Inhibition of LSD1 in MDS progenitors restores differentiation of CD141 Hi conventional dendritic cells

Leukemia. 2020 Sep;34(9):2460-2472. doi: 10.1038/s41375-020-0765-5. Epub 2020 Feb 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / immunology*
  • Cell Differentiation* / genetics
  • Dendritic Cells / cytology*
  • Dendritic Cells / immunology
  • Epigenesis, Genetic
  • Female
  • Histone Demethylases / antagonists & inhibitors*
  • Histone Demethylases / metabolism
  • Humans
  • Interferon Regulatory Factors / metabolism
  • Mice
  • Mice, Knockout
  • Myelodysplastic Syndromes / pathology*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*

Substances

  • Antigens, Surface
  • Interferon Regulatory Factors
  • THBD protein, human
  • interferon regulatory factor-8
  • Histone Demethylases
  • KDM1A protein, human