TY - JOUR
T1 - Inhibition of LSD1 in MDS progenitors restores differentiation of CD141Hi conventional dendritic cells
AU - Srivastava, Pragya
AU - Tzetzo, Stephanie L.
AU - Gomez, Eduardo Cortes
AU - Eng, Kevin H.
AU - Jani Sait, Sheila N.
AU - Kuechle, Joseph B.
AU - Singh, Prashant K.
AU - De Jong, Kitty
AU - Wiatrowski, Kyle R.
AU - Peresie, Jennifer
AU - Dimitroff, Ava
AU - Lynch, Miranda L.
AU - Wang, Jianmin
AU - Abrams, Scott I.
AU - Griffiths, Elizabeth A.
AU - Nemeth, Michael J.
N1 - Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85089879503
U2 - 10.1038/s41375-020-0765-5
DO - 10.1038/s41375-020-0765-5
M3 - Article
C2 - 32099035
SN - 0887-6924
VL - 34
SP - 2460
EP - 2472
JO - Leukemia
JF - Leukemia
IS - 9
ER -