SNU team opens way for customized cure of acute myeloma leukemia

Korean researchers have successfully developed a treatment-predicting biomarker for acute myeloid leukemia (AML).

A joint research team from Seoul National University Hospital and Seoul National University said Monday that they have developed a biomarker predicting treatment, which offers the possibility of personalized treatment for AML patients.

Professors Koh Young-il and Byun Ja-min of the Department of Hematology/Oncology at Seoul National University Hospital, Professor Yoon Tae-young of the School of Life Sciences at Seoul National University (with researcher Jeon Chang-joo), and his startup PROTEINA said they have developed a high-performance companion diagnostic biomarker that can predict the therapeutic effect of ABT-199 (Venetoclax) targeted anticancer drug by analyzing the interaction between BCL2 protein and other proteins through single-molecule co-immunoprecipitation (SMPC) technology.

AML is a type of blood cancer in which abnormal white blood cells in the blood or bone marrow rapidly proliferate and interfere with the production of normal blood cells, making rapid and effective treatment selection critical.

BH3 mimetics targets the BCL2 protein to induce the death of cancer cells, and ABT-199 (Venetoclax) in particular has shown promise in treating AML. However, not all patients respond equally well to treatment, and some develop resistance after a temporary remission, so a way to predict the effectiveness of ABT-199 in advance was needed.

The researchers developed a technique to detect quantitatively 22 different protein-protein interaction (PPI) signals by analyzing nearly 30,000 cells using single-molecule pull-down, co-immunoprecipitation, and single-molecule fluorescence imaging techniques. This allowed them to measure accurately how different proteins interact with each other.

The team found that ABT-199 selectively binds to the BCL2 protein and disassembles the BCL2-BAX complex and that the activated BAX protein induces cancer cell death. This identified a key mechanism by which ABT-199 kills cancer cells.

It then obtained multidimensional PPI profile data from 32 AML patients' samples and analyzed the correlation with drug reactivity at the ex vivo level. The results revealed key protein complexes that influence the sensitivity (how well it works) and resistance (how well it resists) of ABT-199.

Notably, the researchers found that the BCL2-BAX complex was associated with sensitivity to ABT-199 and the BCLxL-BAK complex with resistance.

Based on this data, the team developed a high-performance companion diagnostic biomarker predicting an individual AML patient's response to ABT-199. The biomarker looks at how certain PPI signaling changes in a patient's cells and can accurately predict whether ABT-199 will work.

The team tested the predictive accuracy of the developed biomarker at the ex vivo level. The results showed a predictive accuracy (AUC-ROC) of up to 94 percent, good enough for clinical application.

In a clinical test on 10 real AML patients, the biomarker successfully predicted the chemotherapy response of 9 of them, with a sensitivity of 100 percent and a specificity of 83.3 percent, confirming that it can predict patients' anticancer drug responsiveness with high accuracy.

"The single-molecule co-immunoprecipitation technique is a tool that can precisely measure protein-protein interactions (PPIs) in various samples," Professor Yoon said. "It is expected to open up new avenues for molecular diagnostics by understanding complex protein interaction networks."

Professor Koh also said, "This study highlights the importance of ABT-199 (Venetoclax) therapy in acute myeloid leukemia, a disease that has previously lacked predictive biomarkers for response. This PPI profiling-based study will contribute significantly to the development of precision medicine for acute myeloid leukemia in the future."

The findings are published in the latest issue of the prestigious journal Nature Biomedical Engineering.