Inhibition of LSD1 in MDS Progenitors Restores Differentiation of CD141(Hi) Conventional 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, CD141(Hi) conventional dendritic cells (CD141(Hi) cDCs) are necessary for anti-tumor immunosurveillance and the response to immunotherapy. Here, we found that CD141(Hi) cDCs are reduced in MDS bone marrow and based on the premise established in solid tumors, we hypothesized that reduced numbers of CD141(Hi) cDCs are associated with inferior overall survival in MDS patients. We found that MDS patients with reduced numbers of CD141(Hi) cDCs, but not other DC populations, showed reduced overall survival. To examine the basis for reduction in CD141(Hi) 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 CD141(Hi) cDC differentiation. To rescue impaired CD141(Hi) cDC differentiation, we used pharmacologic inhibition of lysine-specific demethylase 1A (LSD1) to promote CD141(Hi) cDC differentiation by MDS progenitors. These data reveal a previously unrecognized element of the MDS immunologic milieu. Epigenetic regulation of CD141(Hi) cDC differentiation offers an intriguing opportunity for intervention and a potential adjunct to immunotherapy for patients with MDS.