Characterization of TRKA signaling in acute myeloid leukemia

Abstract

Tropomyosin-related kinase A (TRKA) translocations have oncogenic potential and have been found in rare cases of solid tumors. Accumulating evidence indicates that TRKA and its ligand, nerve growth factor (NGF), may play a role in normal hematopoiesis and may be deregulated in leukemogenesis. Here, we report a comprehensive evaluation of TRKA signaling in normal and leukemic cells. TRKA expression is highest in common myeloid progenitors and is overexpressed in core binding factor and megakaryocytic leukemias, especially Down syndrome-related AML. Importantly, NGF can rescue GM-CSF dependent TF-1 AML cells, but does not drive proliferation in other TRKA-expressing lines. Although TRKA expression is heterogeneous between and within AML samples, NGF stimulation broadly induces ERK signaling, demonstrating the functional ability of AML cells to respond to NGF/TRKA signaling. However, neither shRNA knockdown nor pharmacologic inhibition have significant anti-proliferative effects on human AML cells in vitro and in vivo. Thus, despite functional NGF/TRKA signaling, the importance of TRKA in AML remains unclear.