TY - JOUR
T1 - Lysine specific demethylase 1 inactivation enhances differentiation and promotes cytotoxic response when combined with all-trans retinoic acid in acute myeloid leukemia across subtypes
AU - Smitheman, Kimberly N.
AU - Severson, Tesa M.
AU - Rajapurkar, Satyajit R.
AU - McCabe, Michael T.
AU - Karpinich, Natalie
AU - Foley, James
AU - Pappalardi, Melissa B.
AU - Hughes, Ashley
AU - Halsey, Wendy
AU - Thomas, Elizabeth
AU - Traini, Christopher
AU - Federowicz, Kelly E.
AU - Laraio, Jenny
AU - Mobegi, Fredrick
AU - Ferron-Brady, Geraldine
AU - Prinjha, Rabinder K.
AU - Carpenter, Christopher L.
AU - Kruger, Ryan G.
AU - Wessels, Lodewyk
AU - Mohammad, Helai P.
PY - 2019/6
Y1 - 2019/6
N2 - Lysine specific demethylase 1 (LSD1) is a histone modifying enzyme that suppresses gene expression through demethylation of lysine 4 on histone H3. The anti-tumor activity of GSK2879552 and GSK-LSD1, potent, selective irreversible inactivators of LSD1, has previously been described. Inhibition of LSD1 results in a cytostatic growth inhibitory effect in a range of acute myeloid leukemia cell lines. To enhance the therapeutic potential of LSD1 inhibition in this disease setting, a combination of LSD1 inhibition and all-trans retinoic acid was explored. All-trans retinoic acid is currently approved for use in acute promyelocytic leukemia in which it promotes differentiation of abnormal blast cells into normal white blood cells. Combined treatment with all-trans retinoic acid and GSK2879552 results in synergistic effects on cell proliferation, markers of differentiation, and, most importantly, cytotoxicity. Ultimately the combination potential for LSD1 inhibition and ATRA will require validation in acute myeloid leukemia patients, and clinical studies to assess this are currently underway.
AB - Lysine specific demethylase 1 (LSD1) is a histone modifying enzyme that suppresses gene expression through demethylation of lysine 4 on histone H3. The anti-tumor activity of GSK2879552 and GSK-LSD1, potent, selective irreversible inactivators of LSD1, has previously been described. Inhibition of LSD1 results in a cytostatic growth inhibitory effect in a range of acute myeloid leukemia cell lines. To enhance the therapeutic potential of LSD1 inhibition in this disease setting, a combination of LSD1 inhibition and all-trans retinoic acid was explored. All-trans retinoic acid is currently approved for use in acute promyelocytic leukemia in which it promotes differentiation of abnormal blast cells into normal white blood cells. Combined treatment with all-trans retinoic acid and GSK2879552 results in synergistic effects on cell proliferation, markers of differentiation, and, most importantly, cytotoxicity. Ultimately the combination potential for LSD1 inhibition and ATRA will require validation in acute myeloid leukemia patients, and clinical studies to assess this are currently underway.
KW - acute myeloid leukemia
KW - all-trans retinoic acid
KW - lysine specific demethylase 1 (LSD1)
UR - http://www.scopus.com/inward/record.url?scp=85066961953&partnerID=8YFLogxK
U2 - 10.3324/haematol.2018.199190
DO - 10.3324/haematol.2018.199190
M3 - Article
SN - 0390-6078
VL - 104
SP - 1156
EP - 1167
JO - Haematologica
JF - Haematologica
IS - 6
ER -
