Fyn Upregulation Is a Novel ROS-Dependent Mechanism Controlling CML Growth, Progression and Imatinib Resistance.

Abstract

The BCR/ABL kinase alters the oxidative environment in chronic myelogenous leukemia (CML) cells, but the consequences of the increased reactive oxygen species (ROS) levels on signaling pathways remain unknown. Increased intracellular peroxides in BCR/ABL expressing cells have been linked to DNA damage, which may promote blast crisis in CML. We report that Fyn is a BCR/ABL target that is upregulated in an oxidant- sensitive manner. Cells overexpressing BCR/ABL display a four-fold upregulation of Fyn protein, which is blocked by chemical antioxidants. This increase in Fyn directs proliferative and survival signals since knockdown of Fyn using shRNA slows leukemia cell growth by 50% both in vitro and in vivo, inhibits clonogenic growth by 45% and leads to increased sensitivity to imatinib. Jak2 inhibition prevents Fyn protein upregulation, suggesting that Jak2 is upstream of Fyn, and we indeed find that Jak2 levels are increased in BCR/ABL expressing cells. In a cohort of CML patients Fyn expression was significantly increased in blastic phase CML samples as compared to chronic phase, confirming the clinical relevance of Fyn upregulation. Collectively, these results demonstrate that oxidant-dependent, Jak2-dependent upregulation of Fyn is a novel alteration in CML that is critical for cell growth and imatinib resistance.