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FTY720 induces apoptosis of M2 subtype acute myeloid leukemia cells by targeting sphingolipid metabolism and increasing endogenous ceramide levels.
- Source :
-
PloS one [PLoS One] 2014 Jul 22; Vol. 9 (7), pp. e103033. Date of Electronic Publication: 2014 Jul 22 (Print Publication: 2014). - Publication Year :
- 2014
-
Abstract
- The M2 subtype Acute Myeloid Leukemia (AML-M2) with t(8;21) represents an unmet challenge because of poor clinical outcomes in a sizable portion of patients. In this study,we report that FTY720 (Fingolimod), a sphingosine analogue and an FDA approved drug for treating of multiple sclerosis, shows antitumorigenic activity against the Kasumi-1 cell line, xenograft mouse models and leukemic blasts isolated from AML-M2 patients with t(8;21) translocation. Primary investigation indicated that FTY720 caused cell apoptosis through caspases and protein phosphatase 2A (PP2A) activation. Transcriptomic profiling further revealed that FTY720 treatment could upregulate AML1 target genes and interfere with genes involved in ceramide synthesis. Treatment with FTY720 led to the elimination of AML1-ETO oncoprotein and caused cell cycle arrest. More importantly, FTY720 treatment resulted in rapid and significant increase of pro-apoptotic ceramide levels, determined by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry based lipidomic approaches. Structural simulation model had also indicated that the direct binding of ceramide to inhibitor 2 of PP2A (I2PP2A) could reactivate PP2A and cause cell death. This study demonstrates, for the first time, that accumulation of ceramide plays a central role in FTY720 induced cell death of AML-M2 with t(8;21). Targeting sphingolipid metabolism by using FTY720 may provide novel insight for the drug development of treatment for AML-M2 leukemia.
- Subjects :
- Animals
Caspases metabolism
Cell Line
Core Binding Factor Alpha 2 Subunit genetics
Fingolimod Hydrochloride
Gene Expression Regulation, Leukemic drug effects
Humans
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute pathology
Mice, Nude
Models, Molecular
Oncogene Proteins, Fusion genetics
Protein Phosphatase 2 metabolism
RUNX1 Translocation Partner 1 Protein
Sphingosine therapeutic use
Antineoplastic Agents therapeutic use
Apoptosis drug effects
Ceramides metabolism
Leukemia, Myeloid, Acute drug therapy
Propylene Glycols therapeutic use
Sphingolipids metabolism
Sphingosine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25050888
- Full Text :
- https://doi.org/10.1371/journal.pone.0103033