ABSTRACT
The lack of a clear understanding of the pathophysiology of Cutaneous T cell Lymphoma
(CTCL) and in particular its aggressive leukemic form Sézary Syndrome, has impeded
therapeutic advances, and current treatments are only palliative. Although CTCL is a relatively
rare disease, Moffitt Cancer Center Malignant Hematology and USF Dermatology Departments
manages about 100 new patients with CTCL annually. This study represents a concerted effort
by a team of clinical investigators and translational immunologists at Moffitt to identify new
effective treatments for CTCL patients with aggressive disease, based on the discovery of key
molecular regulators of Sézary Syndrome development and growth. Specifically, our new
mouse models indicate that Special AT-rich region binding protein 1 (SATB1), a master
genomic organizer and a key regulator of T-cell development and maturation, prevents mature T
cell malignization by repressing crucial pathogenic drivers of Sézary cells. Our central
hypothesis is that SATB1 acts as a tumor suppressor in CTCL, by repressing STAT5 activation,
chemokine receptors that govern T cell homing to the skin and transcription factors commonly
de-regulated in malignant T cells. Accordingly, restoring SATB1 expression by targeting histone
methylation and de-acetylation will avert the malignant phenotype of Sézary cells. We will
leverage a growing collection of aphaeresis specimens and unique mouse models to dissect the
epigenetic mechanisms governing the pathogenesis of Sézary Syndrome, with the overarching
goal of subsequently targeting them through more effective interventions in our clinic.
In Aim 1, we will elucidate how SATB1 silencing drives the pathogenesis of CTCL. Based on
our preliminary results, our hypothesis is that Satb1 silencing cooperates with Notch signaling to
elicit a STAT5-, CCR10-, IKZF2/HELIOS-dependent transcriptional program leading to the
progressive expansion, skin homing and malignant transformation of post-thymic CD4 T cells.
In Aim 2, we will define the complementary mechanisms leading to epigenetic silencing of
the SATB1 locus in Sézary Syndrome. We will test the hypothesis that SATB1 is silenced in
Sézary cells through a combination of histone methylation at K27 and K9 that, along with and
lysine de-acetylation, resulting in significant changes in chromatin accessibility.
In Aim 3, we will leverage our new biological understanding to identify the combination of
epigenetic drugs that more effectively restore SATB1 expression and thwart oncogenic signals
in Sézary cells.
Our work will exert a profound effect in the field by elucidating how epigenetic repression of
the master genomic organizer SATB1 governs the malignant transformation of mature CD4 T
cells in coordination with NOTCH signaling, leading to fatal skin accumulation of lymphocytes in
Sézary patients. This mechanistic insight will inform the most effective combination of drugs
needed to de-repress the SATB1 locus and antagonize oncogenic signals, which will overturn
malignant Sézary cells. This biological understanding will be followed by clinical interventions at
Moffitt for patients with aggressive CTCL, including Sézary Syndrome.