Epiproteomic profiling of Sézary Syndrome

Cutaneous T cell lymphomas (CTCL) are rare cancers of the immune system that arise from mature T cells and manifest in the skin. Sézary syndrome (SS) represents the most aggressive form of CTCL and has a poor prognosis with limited effective therapies. Unlike many cancers where we observe recurrent mutations in specific genes, there is a diversity of mutations associated with CTCLs, suggesting that non-genetic or epigenetic mechanisms may play an important role in disease development and progression.

DNA is tightly wound around proteins called histones to form chromatin, a compact structure that organizes the genome of a cell within the nucleus. Specific regions of histones can be chemically modified, allowing cells to regulate which genes are active or silenced. These histone modifications, known as post-translational modifications (PTMs), form an “epigenetic code” interpreted by chromatin-binding proteins that regulate gene expression.
We have previously found mutations in SS affecting proteins that bind chromatin and modify PTMs. To determine whether the epigenetic code itself is altered in SS, we applied a mass spectrometry-based technique to compare histone PTMs in cancerous T cells from SS patients with those from healthy donors. This analysis revealed widespread alterations in histone PTMs, including loss of a poorly characterized modification--histone H3 lysine 18 monomethylation (H3K18me1).

The goal of this project is to define the role of H3K18me1 in Sézary syndrome. We will map where H3K18me1 enriches across the genome to identify genes that may be regulated by this modification. We are also investigating the proteins that add (“writers”), remove (“erasers”) and recognize (“readers”) the H3K18me1 modification. Notably, we have identified a candidate reader, SCML2, which we believe binds to H3K18me1 and contributes to the development of CTCL.

Overall, this research seeks to understand how changes in histone modifications like H3K18me1 cause T cell lymphoma. If successful, this work could yield new blood tests to detect this disease and identify and reveal new drug targets for patients with T cell lymphoma.