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Acute Lymphoblastic Leukemia Study Explores Role of DNA Methylation in Outcomes, Treatment

NEW YORK – Researchers in Europe studied the association between DNA methylation status in acute lymphoblastic leukemia patients and clinical outcomes and found a patient subgroup with high hypermethylation that may benefit from a targeted therapy.

In their study, published Wednesday in Science Translational Medicine, the researchers conducted genome-wide DNA methylation analyses on 143 adult ALL samples using the Illumina Infinium MethylationEPIC BeadChip panel. They began by breaking the samples into five subgroups based on methylation status, with cluster one having the lowest DNA methylation and cluster five having the highest DNA methylation.

The researchers probed deeper into the clinical outcomes of patients based on their DNA methylation levels and found that patients in cluster five, with the highest methylation level, and those in cluster one and two, with the lowest methylation, had poorer outcomes.

The five-year overall survival probability was 53 percent for patients in cluster five with high hypermethylation and 50 percent in clusters one and two who had hypomethylation. The remaining patient groups, who were characterized by intermediate hypermethylation, had a 71.5 percent five-year overall survival probability.

The high-hypermethylation and hypomethylation ALL patients also saw decreased event-free survival compared to the intermediate group. Cluster five had a five-year event-free survival probability of 46 percent and the hypomethylation group had a probability of 44 percent, compared to 69 percent for the intermediate group.

On treatment, the hypermethylated group also showed slower response based on prednisone and bone marrow measurements and showed higher postinduction minimal residual disease compared to the hypomethylated group.

Based on the poor outcomes for the hypermethylated group, the researchers performed epigenetic treatment with DNMT inhibitors, or hypomethylating agents, in mouse models. They administered 5-azacytidine, which inhibits DNA methyltransferase, to mice representing each methylation group. In the models based on patient-derived xenografts with intermediate or high hypermethylation, the DNMT inhibitor "significantly increased survival, delayed tumor expansion, and led to marked, albeit transient, decreases in leukemic burdens," the authors wrote. The two models from hypomethylated patient-derived xenografts saw an increase in peripheral blast counts and death on the treatment.

"Although obtained in a limited number of mice, these results indicate the efficacy of DNMT inhibitor treatment in [ALL] with a hypermethylated profile, including those belonging to the poor prognosis C5 cluster," the authors wrote. "Aberrant hypermethylation could be a predictive factor for therapeutic response and the use of hypomethylating agents for a subset of [ALL] with unfavorable prognosis."

The researchers also performed RNA sequencing on 48 ALL samples. The hypermethylated group had the highest number of differentially expressed genes, and the hypomethylated group had the lowest. Oncogenes specific to patients in cluster five included CAPG, RGS17, FAM83A, LGALS, NCR1, and EMP1.

The high hypermethylation in clusters four and five was also associated with tumor suppressor gene inactivation in more than a dozen genes, the researchers found.

The authors noted that further research is needed to confirm the therapeutic potential of treatment with hypomethylating agents and the use of testing for DNA methylation for ALL patients.

"Follow-up studies are necessary to confirm the therapeutic potential of hypomethylating agents in primary patients, including tests for the efficacy of hypomethylating agents in combination with conventional chemotherapy, other epigenetic drugs such as EZH2 inhibitors, or targeted therapies such as BCL2 inhibitors," they wrote.

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