PLK4 Identified as Potential Target for TP53 Mutated Acute Myeloid Leukemia


A research team led by Professor Anskar Leung Yu-hung at the University of Hong Kong has identified polo-like kinase 4 (PLK4) as a promising therapeutic target for acute myeloid leukemia (AML) with the TP53 mutation. AML is a deadly blood cancer that currently has limited treatment options available.

The team’s findings could pave the way for clinical trials aimed at improving outcomes for patients with this specific subtype of AML. Queen Mary Hospital is one of the treatment sites where the effectiveness of a PLK4 inhibitor will be tested in AML patients. The study has been published in the journal Blood.

AML is caused by genetic changes in blood stem cells in the bone marrow. Symptoms of the disease include fever, bleeding, and infection. Without treatment, AML patients can deteriorate rapidly and die. Conventional treatments for AML include intensive chemotherapy and blood stem cell transplantation, but only 40% of patients are able to be cured and have long-term survival.

In the specific subtype of AML with the TP53 mutation, conventional treatments have shown poor response rates, resulting in high mortality within a year of diagnosis. Currently, there are no specific treatment options available for this subtype, highlighting the urgent need for novel and targeted therapies.

By conducting a comprehensive analysis of gene expression and pharmacological vulnerabilities in different AML subtypes, the research team identified the gene PLK4, which is specifically active in TP53 mutated AML. PLK4 is a major regulator of cell division. The study found that TP53 mutated AML is resistant to chemotherapy but highly vulnerable to prolonged PLK4 inhibition. Inhibition of PLK4 also induces DNA damage, cell aging, and abnormal cell division.

Furthermore, the team discovered that a combination of histone modification and polyploidy activates the cGAS-STING pathway, triggering the immune system. These findings were consistently observed in the laboratory setting and animal models. In animal models, the combination of the PLK4 inhibitor with a monoclonal antibody against CD47 enhanced the killing capability of macrophages, resulting in a synergistic reduction of leukemic burden and prolonged animal survival.

This study is the first to demonstrate the therapeutic effect of PLK4 inhibition on TP53 mutated AML and the novel mechanism involving the activation of the cGAS-STING pathway and the immune system. These findings provide a foundation for evaluating the clinical effects of a PLK4 inhibitor in patients with this specific AML subtype.

In addition to hospitals in the United States and Canada, Queen Mary Hospital’s Hematology Division will serve as a treatment site for global clinical trials testing the effects of the PLK4 inhibitor in AML patients

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