The Role of AKT Signaling in T-Cell Acute Lymphoblastic Leukemia Relapse

Abstract

Thousands of children and adults in the United States are diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) annually. Less than 30% of children and 8% of adults will survive relapsed T-ALL. While relapsed tumor is often more aggressive and treatment resistant than primary disease, the genetic and molecular mechanisms underlying relapse are not well understood. In general, leukemias are composed of heterogeneous cells which evolve over time to drive cancer progression, therapy resistance, and ultimately relapse. To elucidate the mechanisms driving relapse in T-ALL, the phenotypic characteristics of individual T-ALL clones were observed over time in a zebrafish model. Several clones evolved increased leukemia propagating cell (LPC) frequency, leading to increased risk of relapse. This evolution was associated with overexpression of AKT in half of the evolved clones. The AKT pathway is likely activated through epigenetic modifications of upstream AKT modulators, and was found to act through mTOR to increase the LPC frequency in T-ALL. Finally, AKT overexpression leads to therapy resistance to dexamethasone, which can be reversed when treatment is combined with an AKT inhibitor.