Comparative DNA Methylation Profiling of Human and Murine ALK-Positive B-Cell Neoplasms

Area of Science:

• Hematology
• Epigenetics
• Oncology

Background:

• Anaplastic lymphoma kinase (ALK) gene fusions define specific T- and B-cell neoplasms, including ALK-positive anaplastic large cell lymphoma (ALCL) and ALK-positive large B-cell lymphoma (LBCL).
• ALK-positive LBCL is a rare, aggressive lymphoma initially recognized as a variant of diffuse LBCL with plasmablastic features.

Purpose of the Study:

• To compare the DNA methylation profiles of human and murine ALK-positive B-cell neoplasms.
• To investigate the epigenetic similarities and differences between ALK-positive LBCL, diffuse LBCL, multiple myeloma, and normal B-cell populations.

Main Methods:

• Comparative DNA methylation profiling using array-based data.
• Analysis of human ALK-positive LBCL samples (n=8) against DLBCL (n=75), multiple myeloma (n=24), ALK-positive ALCL (n=12), and normal B-cells (n=93).
• Examination of epigenetic age and proliferative history, alongside cross-species comparison of murine ALK-positive B-cell neoplasms.

Main Results:

• ALK-positive LBCLs display a distinct DNA methylation signature characterized by lower global methylation levels, similar to multiple myeloma and distinct from DLBCL and normal B-cells.
• DNA methylation alterations in ALK-positive LBCL primarily occurred in heterochromatic and polycomb-repressed regions.
• Epigenetic age and proliferative history of ALK-positive LBCL were intermediate between multiple myeloma and DLBCL. Murine models showed conserved hypomethylated signatures and affected pathways.

Conclusions:

• Human and murine ALK-positive B-cell lymphomas share a hypomethylated epigenetic profile that closely resembles plasma cell neoplasms, rather than diffuse large B-cell lymphoma.
• These findings highlight conserved epigenetic mechanisms across species and suggest a closer relationship between ALK-positive LBCL and plasma cell malignancies.
• The study provides insights into the epigenetic landscape of aggressive B-cell lymphomas, potentially informing future diagnostic and therapeutic strategies.