FTY720 induces apoptosis of M2 subtype acute myeloid leukemia cells by targeting sphingolipid metabolism and increasing endogenous ceramide levels

Limin Chen; Liu-Fei Luo; Junyan Lu; Lianchun Li; Yuan-Fang Liu; Jiang Wang; Hong Liu; Heng Song; Hualiang Jiang; Sai-Juan Chen; Cheng Luo; Keqin Kathy Li

doi:10.1371/journal.pone.0103033

FTY720 induces apoptosis of M2 subtype acute myeloid leukemia cells by targeting sphingolipid metabolism and increasing endogenous ceramide levels

PLoS One. 2014 Jul 22;9(7):e103033. doi: 10.1371/journal.pone.0103033. eCollection 2014.

Authors

Affiliations

¹ State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
² State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁴ Department of Chemistry, East China University of Science and Technology, Shanghai, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects*
Caspases / metabolism
Cell Line
Ceramides / metabolism*
Core Binding Factor Alpha 2 Subunit / genetics
Fingolimod Hydrochloride
Gene Expression Regulation, Leukemic / drug effects
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology
Mice, Nude
Models, Molecular
Oncogene Proteins, Fusion / genetics
Propylene Glycols / therapeutic use*
Protein Phosphatase 2 / metabolism
RUNX1 Translocation Partner 1 Protein
Sphingolipids / metabolism*
Sphingosine / analogs & derivatives*
Sphingosine / therapeutic use

Substances

AML1-ETO fusion protein, human
Antineoplastic Agents
Ceramides
Core Binding Factor Alpha 2 Subunit
Oncogene Proteins, Fusion
Propylene Glycols
RUNX1 Translocation Partner 1 Protein
Sphingolipids
Protein Phosphatase 2
Caspases
Fingolimod Hydrochloride
Sphingosine

Grants and funding

This work was supported by China 973 Program (2013CB733700, 2011CB510102, and 2009CB918502), the National Natural Science Foundation of China grants (81270622, 91029704, 91229204, 21210003, 81230076, 21021063 and 81200373), the National High Technology Research and Development Program of China (2012AA020302), and the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program” (2013ZX09507-004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.