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| Status |
Public on Mar 14, 2012 |
| Title |
Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [Illumina HumanHT-12 gene expression array] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which 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 novel combinatorial therapies of AML.
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| Overall design |
Overall, 30 specimens derived from HL-60 or TEX cell line were treated with drugs and hybridized to Illumina HumanHT-12 gene expression arrays.
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| Contributor(s) |
Schenk T, Chen WC, Göllner S, Howell L, Jin L, Hebestreit K, Klein H, Popescu AC, Burnett A, Mills K, Casero R Jr, Marton L, Woster P, Minden MD, Dugas M, Wang JC, Dick JE, Müller-Tidow C, Petrie K, Zelent A |
| Citation(s) |
22406747 |
| Submission date |
Dec 22, 2011 |
| Last update date |
Aug 13, 2018 |
| Contact name |
Hans-Ulrich Klein |
| E-mail(s) |
h.klein@uni-muenster.de
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| Organization name |
Columbia University Medical Center
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| Department |
Neurology
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| Lab |
Center for Translational and Computational Neuroimmunology
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| Street address |
622 W 168th St
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10032 |
| Country |
USA |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (30)
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| This SubSeries is part of SuperSeries: |
| GSE34726 |
Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia |
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| Relations |
| BioProject |
PRJNA156239 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE34672_RAW.tar |
26.2 Mb |
(http)(custom) |
TAR |
| GSE34672_non-normalized.txt.gz |
7.0 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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