%0 Journal Article %1 schenk2012inhibition %A Schenk, Tino %A Chen, Weihsu Claire %A Göllner, Stefanie %A Howell, Louise %A Jin, Liqing %A Hebestreit, Katja %A Klein, Hans-Ulrich %A Popescu, Andreea C %A Burnett, Alan %A Mills, Ken %A Casero Jr., Robert A %A Marton, Laurence %A Woster, Patrick %A Minden, Mark D %A Dugas, Martin %A Wang, Jean CY %A Dick, John E %A Müller-Tidow, Carsten %A Petrie, Kevin %A Zelent, Arthur %D 2012 %J Nature Medicine %K 4 background cancer epigenetics histones methods %N 4 %P 605-612 %R 10.1038/nm.2661 %T Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia %V 18 %X Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15;17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non-APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine-specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4me2) across the genome, but it did increase H3K4me2 and expression of myeloid-differentiation–associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID γ (with interleukin-2 (IL-2) receptor γ chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.

@article{schenk2012inhibition, abstract = {Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15;17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non-APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine-specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4me2) across the genome, but it did increase H3K4me2 and expression of myeloid-differentiation–associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID γ (with interleukin-2 (IL-2) receptor γ chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.}, added-at = {2017-10-04T04:21:40.000+0200}, author = {Schenk, Tino and Chen, Weihsu Claire and Göllner, Stefanie and Howell, Louise and Jin, Liqing and Hebestreit, Katja and Klein, Hans-Ulrich and Popescu, Andreea C and Burnett, Alan and Mills, Ken and Casero Jr., Robert A and Marton, Laurence and Woster, Patrick and Minden, Mark D and Dugas, Martin and Wang, Jean CY and Dick, John E and Müller-Tidow, Carsten and Petrie, Kevin and Zelent, Arthur}, biburl = {https://www.bibsonomy.org/bibtex/2f08175b4a3ad67955c9eff2dc408e57d/artheibault}, description = {This article describes the leukemia-treatment dataset used by Klein et al. in their study of histone data by ChIP-seq.}, doi = {10.1038/nm.2661}, interhash = {b04f9b1ceeae985ceae96a345d51a4c1}, intrahash = {f08175b4a3ad67955c9eff2dc408e57d}, journal = {Nature Medicine}, keywords = {4 background cancer epigenetics histones methods}, number = 4, pages = {605-612}, timestamp = {2017-10-25T20:51:44.000+0200}, title = {Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia}, volume = 18, year = 2012 }