DNA Pattern Offers Clues into Origin of Aggressive Lymphoma, and Ways of Treating It

DNA Pattern Offers Clues into Origin of Aggressive Lymphoma, and Ways of Treating It

Therapies that interfere with the DNA methylation pattern may be a promising treatment approach for patients with anaplastic large cell lymphoma (ALCL), a new study suggests, demonstrating that ALCL cells have DNA methylation fingerprints that are distinct from those found in healthy T-cells.

The study, “Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling,” published in Cell Reports, provides further insights into the origin of ALCL, a point of some controversy among scientists, with some suggesting it originates from undifferentiated thymus cells.

Epigenetic alterations, such as DNA methylation, are modifications in the DNA that do not affect their sequence, but that can change the rate at which a gene is expressed (meaning the rate at which a gene gives rise to proteins); highly methylated regions of the genome are often expressed at a lower rate, creating fewer of their proteins.

In cancer cells, epigenetic alterations often consist of global loss and local gain of DNA methylation. This affects the expression of specific genes, granting particular advantages to the tumor cells. In addition, studying the methylation pattern of cancer cells can provide scientists with information regarding their origin, as certain methylation sequences are shared between the cancer cell and their cell of origin.

ALCL is an aggressive non-Hodgkin lymphoma (NHL) of T-cell origin that is mostly diagnosed in children and young adults, accounting for 10 percent to 15 percent of pediatric and adolescent NHL. In about 30 percent of ACLC cases, a fusion between the ALK and NPM1 protein is identified, which is believed to lead cells toward malignant transformation.

To understand whether the methylation patterns of ALK-positive ALCL tumors were distinct from those of ALK-negative ALCL, Melanie Hassler, with the Department of Pathology at MedUni Vienna, Division of Experimental Pathology, collaborated with researchers from the Austrian Institute of Technology (AIT), the University of Cambridge, and the University of Southern California (USC).

Although their results showed that all ALCL tumors had similar DNA methylation patterns, irrespective of their ALK status, the DNA methylation fingerprint of these tumors provided important information as to their cellular origin. Contrary to suggestions that ALCL had a post-thymic origin, the researchers found that ALCL cells shared DNA methylation patterns with early T-cell progenitors found in the thymus.

They also found that ALCL cells have a strong methylation in genes that are critical for T-cell development and differentiation. They believe that using DNA methylation inhibitors — which are currently approved for acute myeloid leukemia and myelodysplasic syndrome, and in clinical development for a variety of other cancers — may induce the differentiation of these cells, hampering tumor progression.

“Certain drugs that interfere in the methylation programme of cancer cells could be used in [the] future to adjust the methylation pattern of ALCL cells to that of healthy T-cells, thereby arresting tumour growth,” Hassler said in a press release.

“The results of this study have given us a better understanding of the development of ALCL in children and adolescents, so that in [the] future we will be able to attack cancer cells in a targeted way, using epigenetic therapies,” Egger added. “Furthermore, decoding of the methylation pattern of ALCL provides us with a basis for establishing biomarkers in the area of personalised and translational medicine.”

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