BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition.

Sa Rang Kim,Michael Girardi,Benoit M Cyrenne,Kacie R Carlson,Francine M Foss,Fatima N Mirza,Julia M Lewis,Patrick F Monico

doi:10.18632/oncotarget.25670

Abstract

While several systemic therapies are approved for cutaneous T cell lymphoma (CTCL), a non-Hodgkin lymphoma of skin-homing T cells that may involve lymph nodes and peripheral blood in advanced stages, relapses are common. Mutational analysis of CTCL cells has revealed frequent amplification of the MYC oncogene, and bromodomain and extraterminal (BET) protein inhibitors have been shown to repress MYC expression in various malignancies. Towards a potential novel therapy, we thus sought to examine the effect of BET inhibition on CTCL cells in vitro. Each of the four tested BET inhibitors (JQ1, ABBV-075, I-BET762, CPI-0610) consistently induced dose-dependent decreases in viability of isolated patient-derived CTCL cells and established CTCL cell lines (MyLa, Sez4, HH, Hut78). This effect was synergistically potentiated by combination of BET inhibition with BCL2 inhibition (e.g. venetoclax) or histone deacetylase (HDAC) inhibition (e.g. vorinostat or romidepsin). There was also a marked increase in caspase 3/7 activation when JQ1 was combined with either vorinostat or romidepsin, confirming that the observed synergies are due in major part to induction of apoptosis. Furthermore, MYC and BCL2 expression were each synergistically repressed when CTCL cells were treated with JQ1 plus HDAC inhibitors, suggesting cooperative activities at the level of epigenetic regulation. Taken together, these data indicate that targeting BET proteins in CTCL represents a promising novel therapeutic strategy that may be substantially potentiated by combination with BCL2 or HDAC inhibition.

Highlights

Cutaneous T cell lymphoma (CTCL), including the most common subtypes mycosis fungoides (MF) and Sézary syndrome (SS), represents a group of non-Hodgkin lymphomas of skin-homing, usually CD4+, malignant T cells [1, 2]
We recently showed that venetoclax (ABT-199), a B-cell lymphoma 2 (BCL2)-selective inhibitor approved for relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion, efficiently induces apoptosis in patient-derived cutaneous T cell lymphoma (CTCL) cells in vitro and this effect is synergistically potentiated by combination with histone deacetylase (HDAC) inhibition [23, 24]
bromodomain and extraterminal (BET) protein BRD4 regulates transcription of key genes for cell cycle progression, such as the MYC oncogene that is often amplified in CTCL, by recruiting the positive transcription elongation factor and phosphorylating the C terminal domain serine 2 on RNA polymerase II [25, 28, 29]

Summary

Introduction

Cutaneous T cell lymphoma (CTCL), including the most common subtypes mycosis fungoides (MF) and Sézary syndrome (SS), represents a group of non-Hodgkin lymphomas of skin-homing, usually CD4+, malignant T cells [1, 2]. MF typically presents as cutaneous patches and plaques, but in more advanced disease, malignant T cells may disseminate to the blood, lymph nodes, and viscera [2, 3]. Malignant T cells may comprise the majority of circulating T cells in patients with SS, with a median survival of 2 to 4 years [4,5,6,7]. The malignant T cells show constitutive activation and propensity for T-helper 2 cytokine production [8] that suppresses cellmediated immunity and increases infection risk [1]. Overall response rates to single agent systemic therapies, including the retinoid bexarotene, and histone deacetylase (HDAC) inhibitors vorinostat and romidepsin, range between 20–45% and relapses are not uncommon [10, 11]

Methods

Results

Conclusion