Cutaneous T cell lymphomas (CTCLs) are a group of non-Hodgkin lymphomas that develop from T cells and infect the skin with painful lesions. The two main subtypes of CTCL are fungalides mycosis and Sézary syndrome. CTCLs are very rare, with around six cases per 1 million people each year. It is unclear how CTCL develops, and unfortunately there are few treatment options and no cure.
The Moffitt Cancer Center treats approximately 16% of CTCL patients nationwide. To develop the understanding of how CTCL develops in hopes of developing new therapies, a team of Moffitt immunologists and hematologists, including Jose Conejo-Garcia, Ph.D., Javier Pinilla-Ibarz ,, MD, Ph.D. and Lubomir Sokol, MD, Ph.D., conducted a series of studies. In an article published in The Journal of Clinical Research, they demonstrate that reduced sensitivity of the SATB1 protein contributes to the development of CTCL and that drugs that induce SATB1 relapse may be potential treatment options for this disease.
The SATB1 protein plays an important role in cell death, proliferation and invasion, and has also been shown to be involved in the processes that control T cell differentiation. mycosis fungoides are associated with lower levels of SATB1, suggesting that it may play an important role in the development of this disease.
To understand how SATB1 contributes to CTCL, Moffitt researchers created a mouse model that lacked SATB1 in conjunction with overexpression of NOTCH1, which is known to be involved in CTCL development. The mice developed spleens and enlarged livers, swollen lymph nodes, a high level of T cells and lived for a much shorter time than control mice.
When the researchers examined the skin of mice lacking SATB1, they found CTCL-like properties, suggesting that SATB1 loss cooperates with NOTCH1 to stimulate CTCL development. The researchers confirmed these observations by showing that T cells have lower levels of SATB1 in T cells from patients with Sézary syndrome than cells from healthy donors.
The researchers wanted to mechanically find out how the loss of SATB1 contributes to the development of CTCL in mice by evaluating signal pathways applied both upstream and downstream of SATB1. They performed a series of laboratory experiments to show that SATB1 regulates the downstream protein STAT5 and other protein receptors in T cells that cause their proliferation.
Next, the researchers focused on upstream processes to determine how SATB1 loss occurs in patient samples. They found that a process called epigenetic regulation plays an important role in this loss. In particular, they showed that DNA-regulating proteins called histones become methylated, leading to loss of SATB1 expression. They also found that drugs that inhibit this methylation cause SATB1 reabsorption.
These methylation inhibitors also inhibited the growth of Sézary syndrome cells more effectively than the drug romidepsin, which is commonly used to treat CTCL patients. These observations suggest that drugs that target these methylation processes may be operational options for treating CTCL patients.
The researchers hope that their preclinical studies will lead to clinical trials of methylation inhibitors in CTCL patients.
Our results offer a new perspective on the pathophysiology of CTCL, as well as a mechanistic rationale for targeting histone methyltransferases to prevent malignant enlargement and skin rash in advanced CTCL patients. “
Carly Harro, First Author and Student Study, Cancer Biology Moffitt Ph.D. Program
Source:
H. Lee Moffitt Cancer Center & Research Institute
Magazine Reference:
Harro, CM, et al. (2020) Methyltransferase inhibitors restore SATB1 immune activity against cutaneous T cell lymphoma in mice. Journal of Clinical Research. doi.org/10.1172/JCI135711.