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Published on: June 6, 2025
Acid ceramidase is upregulated in AML and represents a novel therapeutic target
Su-Fern Tan1, Xin Liu2, Todd E Fox3
1Department of Medicine, University of Virginia, Charlottesville, VA, USA.
Abstract:
There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity. Treatment of patient samples and cell lines with AC inhibitor LCL204 reduced viability and induced apoptosis. AC overexpression increased the expression of anti-apoptotic Mcl-1, significantly increased S1P and decreased ceramide. Conversely, LCL204 induced ceramide accumulation and decreased Mcl-1 through post-translational mechanisms. LCL204 treatment significantly increased overall survival of C57BL/6 mice engrafted with leukemic C1498 cells and significantly decreased leukemic burden in NSG mice engrafted with primary human AML cells. Collectively, these studies demonstrate that AC plays a critical role in AML survival through regulation of both sphingolipid levels and Mcl-1. We propose that AC warrants further exploration as a novel therapeutic target in AML.
Insights
Targeting acid ceramidase (AC) offers a new therapeutic strategy for acute myeloid leukemia (AML). Inhibiting AC reduces cancer cell survival and improves outcomes in preclinical models, addressing an unmet need in AML treatment.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Acute myeloid leukemia (AML) lacks novel therapeutics, with standard treatments unchanged for decades.
- Sphingolipid metabolism, specifically ceramide and sphingosine 1-phosphate (S1P) levels, is dysregulated in AML, promoting cancer cell survival.
- Acid ceramidase (AC) regulates ceramide breakdown to sphingosine, a precursor for S1P, and is implicated in cancer progression.
Purpose of the Study:
- To investigate the role of acid ceramidase (AC) in acute myeloid leukemia (AML) blast survival.
- To evaluate the therapeutic potential of AC inhibition in AML models.
Main Methods:
- Transcriptome analysis and enzymatic assays were performed on primary AML cells and cell lines.
- AC activity was inhibited using LCL204 in patient samples, cell lines, and mouse models.
- Sphingolipid levels, Mcl-1 expression, and apoptosis were assessed.
Main Results:
- Primary AML cells exhibit high AC expression and activity, crucial for blast survival.
- AC inhibition with LCL204 reduced AML cell viability, induced apoptosis, and altered sphingolipid metabolism.
- LCL204 treatment led to ceramide accumulation and decreased Mcl-1 via post-translational modifications.
- In vivo studies showed LCL204 significantly improved survival in mice with AML.
Conclusions:
- Acid ceramidase (AC) plays a critical role in AML survival by regulating sphingolipid levels and Mcl-1.
- AC inhibition represents a promising novel therapeutic strategy for AML.
- Targeting AC warrants further investigation for AML treatment.
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