Klin Padiatr 2016; 228 - A15
DOI: 10.1055/s-0036-1582492

Pre-BCR expression predicts sensitivity to SYK inhibition in B-cell acute lymphoblastic leukemia

S Köhrer 1, 2, F Seyfried 2, KM Debatin 2, M Müschen 3, LH Meyer 2, RE Davis 4, JA Burger 1
  • 1Department of Leukemia, MD Anderson Cancer Center, Houston, USA
  • 2Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm; Germany
  • 3Department of Laboratory Medicine, University of California, San Francisco, USA
  • 4Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, USA

Introduction: Recent studies have suggested SYK as target for the treatment of pre-BCR+ B-ALL but whether pre-BCR status constitutes the only predictor for sensitivity to SYK inhibition in B-ALL is discussed controversially.

Methods: We employed a comparative approach of pre-BCR knockout and pharmacologic inhibition of pre-BCR signaling with SYK inhibitors to dissect the requirements for the SYK-dependent survival of B-ALL cells.

Results: Pre-BCR+ ALL requires constitutive signals from the pre-BCR and SYK for proliferation and survival. These signals involve the pre-BCR-dependent activation of SYK and PI3K, resulting in the inactivation of FOXO1 and the deregulation of MYC. Inhibition of pre-BCR signaling with SYK inhibitors reverses these effects and exhibits promising activity in several models of pre-BCR+ ALL.

Conclusion: Pre-BCR expression characterizes a subgroup of B-ALL selectively sensitive to SYK inhibition.