Epigenetic drug combination overcomes bone marrow microenvironment-induced chemprotection in pediatric acute lymphoblastic leukemia via modulation of CD81 and BTK

Abstract

Acute Lymphoblastic Leukemia (ALL) is the most commonly diagnosed cancer in pediatric patients in the United States. While recent advances have improved remission rates to upwards of 95%, ALL is still plagued by relapse in nearly 20% of patients. Patients in relapse are more likely to be refractory and have higher mortality rates (50%). The occurrence of these relapse events can be attributed to the accumulation of epigenetic alterations during leukemogenesis. Modulations in DNA methylation and modification of histone proteins can result in an increased occurrence of chemoresistance. A chemoresistant state can be achieved when malignant cells interact with elements within the bone marrow microenvironment. This is referred to as bone marrow microenvironment-induced chemoprotection (BMC) and is prevalent in hematologic malignancies like ALL. ☐ In this study, I investigate the use of the epigenetic modifiers azacitidine (DNA methyltransferase inhibitor) and panobinostat (histone deacetylase inhibitor) in overcoming the effects of BMC in ALL. I identify that these two drugs in combination (aza/pano) have a synergistic killing effect and are not subject to chemoprotective effects when treating ALL cells in direct co-culture with osteoblast-like cells. Minimally cytotoxic concentrations of aza/pano sensitize ALL cells to chemotherapy through a reduction in the surface expression of the tetraspanin protein CD81 and its associated pro-survival signaling through BTK and p53. One cycle of aza/pano treatment in vivo potentiates the effectiveness of subsequent chemotherapy by mobilizing leukemic cells from the bone marrow into the peripheral blood. This study identifies a novel method of improving treatment of ALL via the use of epigenetic sensitization and modulation of CD81 surface expression.