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GATM-Mediated Creatine Biosynthesis Enables Maintenance of FLT3-ITD-Mutant Acute Myeloid Leukemia
Yuan Zhang1, Kimberly J Newsom1, Mei Zhang1
1Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida.
Abstract:
FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia (AML), with the most common mutation being internal tandem duplications (ITD). The presence of FLT3-ITD in AML carries a particularly poor prognosis and renders therapeutic resistance. New druggable targets are thus needed in this disease. In this study, we demonstrate the effects of de novo creatine biosynthesis upregulation by FLT3-ITD on AML sustainability. Our data show that FLT3-ITD constitutively activates the STAT5 signaling pathway, which upregulates the expression of glycine amidinotransferase (GATM), the first rate-limiting enzyme of de novo creatine biosynthesis. Pharmacologic FLT3-ITD inhibition reduces intracellular creatinine levels through transcriptional downregulation of genes in the de novo creatine biosynthesis pathway. The same reduction can be achieved by cyclocreatine or genetic GATM knockdown with shRNA and is reflected in significant decrease of cell proliferation and moderate increase of cell apoptosis in FLT3-ITD-mutant cell lines. Those effects are at least partially mediated through the AMPK/mTOR signaling pathway. This study uncovers a previously uncharacterized role of creatine metabolic pathway in the maintenance of FLT3-ITD-mutant AML and suggests that targeting this pathway may serve as a promising therapeutic strategy for FLT3-ITD-positive AML. IMPLICATIONS: FLT3-ITD mutation in AML upregulates de novo creatine biosynthesis that we show can be suppressed to diminish the proliferation and survival of blast cells.
Insights
FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplications (ITD) in acute myeloid leukemia (AML) upregulate creatine biosynthesis. Targeting this pathway may offer a new therapeutic strategy for FLT3-ITD-positive AML.
Area of Science:
- Hematology
- Cancer Biology
- Metabolic Pathways
Background:
- FMS-like tyrosine kinase 3 (FLT3) mutations, particularly internal tandem duplications (ITD), are common in acute myeloid leukemia (AML).
- FLT3-ITD mutations are associated with poor prognosis and therapeutic resistance in AML patients.
- There is a critical need for novel therapeutic targets in FLT3-mutated AML.
Purpose of the Study:
- To investigate the role of de novo creatine biosynthesis in the sustainability of FLT3-ITD-mutant AML.
- To explore the potential of targeting the creatine metabolic pathway as a therapeutic strategy for FLT3-ITD-positive AML.
Main Methods:
- Analysis of FLT3-ITD effects on STAT5 signaling and glycine amidinotransferase (GATM) expression.
- Assessment of pharmacologic FLT3-ITD inhibition and cyclocreatine treatment on creatine levels, cell proliferation, and apoptosis.
- Evaluation of genetic GATM knockdown using shRNA.
- Investigation of the involvement of the AMPK/mTOR signaling pathway.
Main Results:
- FLT3-ITD constitutively activates STAT5, upregulating GATM and de novo creatine biosynthesis.
- Pharmacologic FLT3-ITD inhibition and cyclocreatine treatment reduced intracellular creatinine levels and GATM expression.
- Genetic GATM knockdown also decreased creatine levels.
- Reduced creatine levels led to decreased cell proliferation and increased apoptosis in FLT3-ITD-mutant AML cell lines, partly via the AMPK/mTOR pathway.
Conclusions:
- FLT3-ITD upregulates de novo creatine biosynthesis, contributing to AML cell maintenance.
- Targeting the creatine metabolic pathway, by inhibiting FLT3 or GATM, reduces proliferation and survival of FLT3-ITD-mutant AML cells.
- The creatine metabolic pathway represents a promising therapeutic target for FLT3-ITD-positive AML.
