Klin Padiatr 2016; 228 - A18
DOI: 10.1055/s-0036-1582495

Efficacy of the BH3-mimetic ABT-199 in acute lymphoblastic leukemia

R Hörl 1, F Seyfried 1, S Demir 1, J Zinngrebe 1, S Köhrer 1, KM Debatin 1, LH Meyer 1
  • 1Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm

Introduction: Acute lymphoblastic leukemia (ALL) cells can evade from apoptosis by upregulating anti-apoptotic proteins. Mcl-1 and Bcl-2 are frequently overexpressed in ALL, thus, appearing as promising targets for anti-ALL therapy.

Methods: In vitro/ex vivo exposure of cell lines and primary patient-derived xenograft samples (pdx) to ABT-199, Dinaciclib and chemotherapy, assessment of cellular viability, generation of Mcl-1 knockout cell lines by CRISPR/Cas9, Western blot, NOD/SCID human ALL mouse model.

Results: 4/6 cell lines and 14/16 pdx samples were highly sensitive to ABT-199. Resistance was associated with an increased Mcl-1:Bcl-2 protein ratio and could be overcome by Mcl-1 knockout or combination treatment with Dinaciclib. Moreover, combination of ABT-199 with chemotherapy (Vincristine, Dexamethasone, Asparaginase) revealed synergistic effects in vitro and in pdx samples ex vivo. Importantly, ABT-199 effectively decreased tumor loads pre-clinically in vivo.

Conclusion: We provide evidence that ABT-199 is a promising agent for treatment of pediatric ALL as it effectively kills human ALL cells in vitro, ex vivo and in vivo.