Epigenetic drug combination overcomes osteoblast-induced chemoprotection in pediatric acute lymphoid leukemia

- Azacitidine and panobinostat have a synergistic killing effect on ALL cells.
- Direct contact between ALL cells and osteoblasts is required for chemoprotection.
- Azacitidine/panobinostat pre-treatment overcomes osteoblast-induced chemoprotection.
- Effects can be replicated ex vivo across a wide variety of primary patient samples.

Although there has been much progress in the treatment of acute lymphoblastic leukemia (ALL), decreased sensitivity to chemotherapy remains a significant issue. Recent studies have shown how interactions with the bone marrow microenvironment can protect ALL cells from chemotherapy and allow for the persistence of the disease. Epigenetic drugs have been used for the treatment of ALL, but there are no reports on whether these drugs can overcome bone marrow-induced chemoprotection. Our study investigates the ability of the DNA methyltransferase inhibitor azacitidine and the histone deacetylase inhibitor panobinostat to overcome chemoprotective effects mediated by osteoblasts. We show that the combination of azacitidine and panobinostat has a synergistic killing effect and that this combination is more effective than cytarabine in inducing ALL cell death in co-culture with osteoblasts. We also show that this combination can be used to sensitize ALL cells to chemotherapeutics in the presence of osteoblasts. Finally, we demonstrate that these effects can be replicated ex vivo in a number of mouse passaged xenograft lines from both B-ALL and T-ALL patients with varying cytogenetics. Thus, our data provides evidence that azacitidine and panobinostat can successfully overcome osteoblast-induced chemoprotection in vitro and ex vivo in both B-ALL and T-ALL cells.

98