An innovative method for identifying acute myeloid leukemia (AML) through the detection of KMT2A gene fusions is poised to significantly improve diagnostic and therapeutic approaches, marking a significant advancement in leukemia research.

The study emphasizes the importance of accurately identifying specific molecular markers in leukemia cells, which can greatly refine the assessment of measurable residual disease (MRD). This development is expected to lead to more informed treatment choices and consequently, better patient outcomes.

A recent publication in The Journal of Molecular Diagnostics by Elsevier highlights a newly developed assay that targets a distinct molecular marker in AML patients. This method could transform the diagnosis and treatment of AML, especially in cases involving KMT2A gene fusions. The assay has the potential to influence treatment decisions, monitor response to therapy, and aid in ongoing disease surveillance.

Each year, approximately 120,000 people worldwide are diagnosed with AML, a rare and aggressive form of blood cancer. Detecting MRD during treatment is crucial for prognosis and guiding treatment strategies. Current MRD detection methods in AML treatment include bone marrow morphology, multiparameter flow cytometry (MPFC), and DNA sequencing.

Morphological assessment can identify leukemic cells only when they constitute 5% of the sample. MPFC offers higher sensitivity (0.01% to 0.001%) but is complex in both implementation and interpretation and lacks standardization across labs. DNA sequencing can detect leukemic cells through their mutation profiles but is costly and can be affected by clonal hematopoiesis in non-leukemic cells.

Significant Progress in Leukemia Research

Grant A. Challen, Ph.D., from the Division of Oncology at the Washington University School of Medicine in St. Louis, notes the significance of oncogenic fusions as disease markers, which are generally absent in healthy cells. Similar tracking methods have already transformed chronic myeloid leukemia (CML) treatment. The KMT2A fusion, a key marker in AML, could similarly aid in sensitive MRD detection, prompting the development of a platform for efficient detection of KMT2A fusions.

The team created a novel droplet digital PCR assay for sensitive detection of KMT2A fusions with its five most common partners. Although there are over 80 known KMT2A fusion partners, the majority involve just five — AF9, AF6, AF4, ELL, and ENL. The assay was validated using human cell lines and patient samples, demonstrating its efficacy in detecting KMT2A fusions.

This method partitions cDNA molecules into microfluidic droplets for analysis with specific primers and probes, producing signals only when fusion transcripts exist. The assay can be expanded to include various oncogenic fusions, enhancing its application in detecting different leukemia types.

Potential Impact on AML Treatment and Future Research

Dr. Challen highlights the assay’s accuracy, noting its lack of false positives in healthy samples and its adaptability for additional oncogenic fusions. This could significantly affect treatment decisions and response evaluations. Determining treatment efficacy is crucial for making critical decisions about therapy intensification or pursuing hematopoietic stem cell transplant.

He emphasizes the assay’s robustness in sensitive KMT2A fusion detection, its practical applicability in disease detection in leukemia patients, and its potential in filling gaps in oncogenic fusion detection. The scalability of the assay allows for broader coverage of oncogenic fusions, symbolizing an improvement in blood cancer detection.

The research, published as “Droplet Digital PCR for Oncogenic KMT2A Fusion Detection” by Andrew L. Young, Hannah C. Davis, and Grant A. Challen on 7 October 2023, was supported by the National Institutes of Health and the Leukemia and Lymphoma Society.

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More about AML Detection Assay

• The Journal of Molecular Diagnostics
• Washington University School of Medicine in St. Louis
• National Institutes of Health
• Leukemia and Lymphoma Society
• Overview of Acute Myeloid Leukemia
• Advances in Leukemia Research
• Droplet Digital PCR Technology
• Bone Marrow Morphology in AML
• Multiparameter Flow Cytometry (MPFC) in Leukemia Detection
• DNA Sequencing in Cancer Research
• Understanding Measurable Residual Disease (MRD)
• KMT2A Gene Fusions and Leukemia