Inhibition of LSD1 in MDS progenitors restores differentiation of CD141Hiconventional dendritic cells

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, CD141Hiconventional dendritic cells (CD141HicDCs) are necessary for antitumor immunosurveillance and the response to immunotherapy. Here, we found that CD141HicDCs are reduced in MDS bone marrow and based on the premise established in solid tumors, we hypothesized that reduced numbers of CD141HicDCs are associated with inferior overall survival in MDS patients. We found that MDS patients with reduced numbers of CD141HicDCs, but not other DC populations, showed reduced overall survival. To examine the basis for reduction in CD141HicDCs, 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 CD141HicDC differentiation. To rescue impaired CD141HicDC differentiation, we used pharmacologic inhibition of lysine-specific demethylase 1A (LSD1) to promote CD141HicDC differentiation by MDS progenitors. These data reveal a previously unrecognized element of the MDS immunologic milieu. Epigenetic regulation of CD141HicDC differentiation offers an intriguing opportunity for intervention and a potential adjunct to immunotherapy for patients with MDS.