The Ectopic Expression of Meiosis Regulatory Genes in Cutaneous T-Cell Lymphomas (CTCL)

Abstract

Cancer testis (CT) antigens, under normal circumstances are uniquely expressed in testicular germ cells. Recent research has shown that meiosis-specific CT (meiCT) antigens are ectopically expressed in cutaneous T-cell lymphoma (CTCL) and may contribute to increased genomic instability. The aberrant activation of meiosis genes in a mitotic cell is now recognized as a distinctive process, "meiomitosis." We have previously demonstrated the ectopic expression of several meiCT antigens in nine patient-derived CTCL cell lines and in expanded peripheral T lymphocytes isolated from Sézary Syndrome patients. In this study we analyzed the transcriptional expression of meiCT genes in Sézary Syndrome patients and healthy controls using publicly-available RNA sequencing (RNA-Seq) data. We corroborated our in silico analysis by examining the expression of 5 meiCT proteins in formalin-fixed, paraffin-embedded (FFPE) lesional samples from CTCL patients. Our results show significant differential gene expression of STAG3, SGO2, SYCP3, and DMC1 in a cohort of Sézary Syndrome patients when compared to healthy controls. Additionally, our study demonstrates a heterogenous expression of meiCT genes involved in initiation (STRA8), sister chromatin cohesion (STAG3, SGO2), homologous chromosome synapsis (SYCP3) and homologous recombination (DMC1) in atypical lymphocytes in FFPE samples. Our results further confirm the ectopic expression of meiCT genes in CTCL which indicates that CTCL malignant cells likely undergo the process of cancer meiomitosis, as opposed to a typical mitotic division. The ectopic expression of meiCT genes together with investigations into the functional mechanisms of cancer meiomitosis will help provide a foundation to develop novel diagnostic tests to distinguish CTCL from benign inflammatory dermatoses and may enable us to develop additional targeted therapies for patients with this malignancy.

Keywords: Sézary Syndrome (SS); cancer/testis antigens; cutaneous T-cell lymphomas (CTCL); germ cell proteins; meiCT; meiomitosis; mycosis fungoides (MF).

Figure 1

RNA-Seq gene expression of meiCT genes (A) STRA8, (B) STAG3, (C) SGO2, (D) SYCP3, and (E) DMC1 in Sézary Syndrome patients compared to normal/control subjects based on pooled data from Choi et al. (12) and Ungewickell et al. (16) datasets. Data was normalized to a mean TPM value for each cohort. Asterisks indicate statistical significance.

Figure 2

Immunohistochemistry staining of STRA8 in (A) normal human testis (positive control), (B) normal skin (C) stage IB MF lesional skin, (D) stage IA MF lesional skin. (E) Sézary Syndrome (F) CD8⁺ MF lesional skin. Scale bars are 50 μm. Nuclear staining in malignant lymphocytes is highlighted (red arrow).

Figure 3

Immunohistochemistry staining of STAG3 in (A) normal human testis (positive control), (B) normal skin (C) stage IIA MF lesional skin, (D) stage IB MF lesional skin. (E) Sézary Syndrome (F) CD8⁺ MF lesional skin. Scale bars are 50 μm. Red arrow highlights cytoplasmic staying of this protein in a number of cells.

Figure 4

Immunohistochemistry staining of SGO2 in (A) normal human testis (positive control), (B) normal skin (C) stage IIA MF lesional skin, (D) CD8⁺ MF lesional skin, (E) Sézary Syndrome (F) peripheral T-Cell Lymphoma. Scale bars are 50 μm. Nuclear staining in malignant lymphocytes is highlighted (red arrow).

Figure 5

Immunohistochemistry staining of SYCP3 in (A) normal human testis (positive control), (B) normal skin (C) stage IB MF lesional skin, (D) stage IB MF lesional skin, (E) Sézary Syndrome (F) stage IA MF lesional skin. Scale bars are 50 μm. Nuclear>cytoplasmic staining in malignant lymphocytes is highlighted (red arrow).

Figure 6

Immunohistochemistry staining of DMC1 in (A) normal human testis (positive control), (B) normal skin (C) stage IA MF lesional skin, (D) stage IA MF lesional skin, (E) Sézary Syndrome (F) CD8⁺ MF lesional skin. Scale bars are 50 μm. Nuclear staining in malignant lymphocytes is highlighted (red arrow).