Abstract 4471: Overcoming the resistance to the anti CD20 treatments in chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia is the most common leukaemia in the Western countries. Treatment of CLL and other lymphomas is based on cytostatic drugs in combination with rituximab or other monoclonal antibodies targeting the B-cell surface marker CD20. Although the CD20-antibodies have revolutionized the therapeutic perspectives of indolent B-cell lymphomas, the treatment of CLL with CD20-antibodies is often inefficient, a feature which has been explained by the inherently low CD20 expression in CLL. It has been shown previously that CD20 is epigenetically regulated in some lymphoma cell lines and that some histone deacetylase inhibitors (HDACi) can increase CD20 expression in B-cell lymphomas both in vitro and in vivo. Therefore, we utilized the HDACi valproate to upregulate CD20 both in CLL cell lines and in patients.Two CLL patients with del13q were treated with valproate at serum levels around 800 μM for three days in three 21-day cycles. CD20 expression was analyzed by Real time-PCR and flowcytometry on the B-CLL cells isolated from peripheral blood.In addition, the valproate-induced histone modifications and changes in repressor/activator complexes of the CD20 promoter were investigated in the CLL cell lines and in patients.In the patient 1, CD20 expression was increased 2 times after 2 weeks of treatment, suggesting long-term effects by valproate. Neither the mRNA stability nor the protein stability seems to be affected by Valproate, suggesting transcriptional effects. However, no effects were observed in the patient 2. In contrast to patient results, Valproate increases CD20 transcript and protein levels by 2,5 times in the CLL-cell line I83-E95 after 48 hours. Here, the activating histone mark, acetylated H3K9, is enriched on the CD20 promoter suggesting valproate-related effects on the epigenome. Our study will continue the characterization of valproate-related effects on the epigenetic signatures of the CD20 promoter in CLL cells in vitro and in vivo, dissecting the mechanisms underling low CD20 expression in CLL. Citation Format: Annarita Scialdone, Jesper Kofoed Damm, Urban Gullberg, Kristina Drott. Overcoming the resistance to the anti CD20 treatments in chronic lymphocytic leukaemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4471.