Klin Padiatr 2014; 226 - A8
DOI: 10.1055/s-0034-1374829

Regulating the activity of p38α/β as a potential therapy against childhood acute lymphoblastic leukemia

A Alsadeq 1, S Strube 1, S Krause 1, M Carlet 2, I Jeremias 2, C Vokuhl 3, S Loges 4, JA Aguirre-Ghiso 5, G Cario 1, M Stanulla 1, 6, M Schrappe 1, DM Schewe 1
  • 1Department of General Pediatrics, ALL-BFM Study Group, University Hospital Schleswig-Holstein, Kiel, Germany
  • 2Helmholtz-Zentrum, Department of Gene Vectors, Munich, Germany
  • 3Department of Childrens' Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
  • 4II. Medical Clinic and Institute of Tumor Biology, University Hospital Eppendorf, Hamburg, Germany
  • 5Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Mount Sinai School of Medicine, New York, NY, 10029, USA
  • 6Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and 15% of the treated patients suffer from relapse. Understanding the biological factors that enhance or inhibit ALL cell proliferation can help in improving the current therapies. During normal hematopoiesis, the MAPK family member p38 mediates growth-inhibitory signals. In this study we have further investigated the role of p38 in ALL biology in vitro and in vivo and found that it plays a pivotal role in ALL proliferation. The growth-kinetics of several ALL cell lines were measured and were correlated with the phosphorylation levels of p38. Most ALL cell lines exhibited a high phosphorylation level of p38 during the log-phase of cell growth. Inhibition of p38, using either SB203580 or BIRB-796, resulted in reduced proliferation of the cells. In addition, ALL cell lines or pediatric ALL primary cells were xenografted into an avian or an NSG-mouse model. The animals were treated with p38-inhibitors. Survival of the animals correlated inversely with the activation of p38. Similar findings were observed in vivo when the cells were transduced with a p38-specific shRNA. Altogether, our data show that p38α/β has a growth-stimulatory role in ALL, and that inhibition of this pathway by small molecule inhibitors or via knock-down approaches suppresses engraftment and prolongs survival of leukemic NSG mice. Accordingly, inhibiting the p38α/β pathway could be used as an adjunct approach in ALL therapy.