Problem

Acute myeloid leukemia (AML), the most common acute leukemia in adults, is a clinically and molecularly heterogeneous disease. Sequencing of large patient cohorts has uncovered a complex mutational landscape in AML but still fails to completely explain the biological and clinical heterogeneity of the pathology. The additional value of non-genetic molecular features, such as epigenetic modifications and patterns, for risk assessment remains largely unexplored

Solution

• Researchers at OSU have developed a novel high-throughput methylation assay, capable of accurately assigning AML patients into epigenetic subtypes (“epitypes”)
• DNA methylation data uncovered that genetically-defined subsets of AML could be expanded to include patients, named ‘epiphenocopies’, who show the same phenotype, DNA methylation pattern and clinical outcome associated with a tumor genetic marker yet lack the specific marker
• Patients that epiphenocopy NPM1 and KMT2A alterations show the same loss of DNA methylation at HOX genomic loci and Menin-dependent activation of HOX genes, thus expanding the proportion of patients that could benefit from Menin inhibitors
• Epiphenocopies of CBF and CEBPA double mutant AML displayed favorable outcomes like the respective genetic markers, thus showing that epiphenocopying of favorable risk genetic markers redefines favorable risk AML patients

Applications

Use of DNA methylation signatures and epitypes to refine AML patients risk stratification and assign specific therapies more effectively

Advantages

• The invention increases the proportion of AML patients that may benefit from targeted Menin inhibition, thus establishing a useful companion biomarker
• DNA methylation signatures improve risk stratification through the identification of patients with epiphenocopies, thus leading to a more effective assignment of patients to existing and novel therapeutic approaches
• AML epitypes have been shown to be highly stable throughout disease course, including following relapse
• Measuring AML epitypes is rapid, cost-effective, robust, high-throughput and requires minimal input material
• The method to evaluate epigenetic subtypes is transferable to many platforms involving various sequencing technologies

Seeking opportunities for out-licensing or collaboration