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Therapeutic Re-Activation of Protein Phosphatase 2A in Acute Myeloid Leukemia
Kavitha Ramaswamy1, Barbara Spitzer1, Alex Kentsis1
1Molecular Pharmacology and Chemistry Program, Department of Pediatrics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, Weill Medical College of Cornell University , New York, NY , USA.
Abstract:
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is required for normal cell growth and development. PP2A is a potent tumor suppressor, which is inactivated in cancer cells as a result of genetic deletions and mutations. In myeloid leukemias, genes encoding PP2A subunits are generally intact. Instead, PP2A is functionally inhibited by post-translational modifications of its catalytic C subunit, and interactions with negative regulators by its regulatory B and scaffold A subunits. Here, we review the molecular mechanisms of genetic and functional inactivation of PP2A in human cancers, with a particular focus on human acute myeloid leukemias (AML). By analyzing expression of genes encoding PP2A subunits using transcriptome sequencing, we find that PP2A dysregulation in AML is characterized by silencing and overexpression of distinct A scaffold and B regulatory subunits, respectively. We review the mechanisms of functional PP2A activation by drugs such as fingolimod, forskolin, OP449, and perphenazine. This analysis yields two non-mutually exclusive mechanisms for therapeutic PP2A re-activation: (i) allosteric activation of the phosphatase activity, and (ii) stabilization of active holo-enzyme assembly and displacement of negative regulatory factors from A and B subunits. Future studies should allow the development of specific and potent pharmacologic activators of PP2A, and definition of susceptible disease subsets based on specific mechanisms of PP2A dysregulation.
Insights
Protein phosphatase 2A (PP2A) is a tumor suppressor. In acute myeloid leukemia (AML), PP2A is functionally inhibited, not genetically mutated, offering therapeutic targets for reactivation.
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- Protein phosphatase 2A (PP2A) is a crucial serine/threonine phosphatase for normal cell growth and development.
- PP2A acts as a tumor suppressor, frequently inactivated in cancer via genetic mutations or deletions.
- In acute myeloid leukemias (AML), PP2A genes are intact, but function is inhibited by post-translational modifications and regulatory subunit interactions.
Purpose of the Study:
- To review molecular mechanisms of PP2A inactivation in human cancers, focusing on AML.
- To analyze PP2A subunit gene expression in AML using transcriptome sequencing.
- To explore therapeutic strategies for PP2A reactivation in AML.
Main Methods:
- Transcriptome sequencing to analyze gene expression of PP2A subunits in AML.
- Review of molecular mechanisms of PP2A inactivation and reactivation.
- Analysis of drug-induced PP2A activation pathways.
Main Results:
- PP2A dysregulation in AML involves silencing of scaffold A subunits and overexpression of regulatory B subunits.
- Functional inhibition of PP2A in AML occurs through post-translational modifications and regulatory interactions.
- Several drugs, including fingolimod and forskolin, can functionally activate PP2A.
Conclusions:
- Therapeutic PP2A reactivation can be achieved through allosteric activation or stabilization of holo-enzyme assembly.
- Targeting PP2A offers a promising therapeutic avenue for AML.
- Future development of specific PP2A activators and identification of susceptible patient subsets are warranted.
